CS232703B2 - Production method of new quinoxaline-1,4-dioxide derivatives - Google Patents
Production method of new quinoxaline-1,4-dioxide derivatives Download PDFInfo
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- CS232703B2 CS232703B2 CS757830A CS783075A CS232703B2 CS 232703 B2 CS232703 B2 CS 232703B2 CS 757830 A CS757830 A CS 757830A CS 783075 A CS783075 A CS 783075A CS 232703 B2 CS232703 B2 CS 232703B2
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- dioxide
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- formylquinoxaline
- align
- acid
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- CKIHZSGJPSDCNC-UHFFFAOYSA-N Quindoxin Chemical class C1=CC=C2N([O-])C=C[N+](=O)C2=C1 CKIHZSGJPSDCNC-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000002253 acid Substances 0.000 claims abstract description 12
- -1 hydroxy, amino, nitro, methoxy Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 28
- JZJFIUXMPBVEFS-UHFFFAOYSA-N 1-oxido-4-oxoquinoxalin-4-ium-2-carbaldehyde Chemical compound C1=CC=C2N([O-])C(C=O)=C[N+](=O)C2=C1 JZJFIUXMPBVEFS-UHFFFAOYSA-N 0.000 abstract description 16
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 6
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical class NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 2
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003307 slaughter Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- NQEWXLVDAVTOHM-UHFFFAOYSA-N 3-nitrobenzohydrazide Chemical compound NNC(=O)C1=CC=CC([N+]([O-])=O)=C1 NQEWXLVDAVTOHM-UHFFFAOYSA-N 0.000 description 1
- LSSUJBFVEXWEEC-UHFFFAOYSA-N 3-phenylpropanehydrazide Chemical compound NNC(=O)CCC1=CC=CC=C1 LSSUJBFVEXWEEC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PKBGHORNUFQAAW-UHFFFAOYSA-N 4-chlorobenzohydrazide Chemical compound NNC(=O)C1=CC=C(Cl)C=C1 PKBGHORNUFQAAW-UHFFFAOYSA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- ZMZGIVVRBMFZSG-UHFFFAOYSA-N 4-hydroxybenzohydrazide Chemical compound NNC(=O)C1=CC=C(O)C=C1 ZMZGIVVRBMFZSG-UHFFFAOYSA-N 0.000 description 1
- REKQLYUAUXYJSZ-UHFFFAOYSA-N 4-methoxybenzohydrazide Chemical compound COC1=CC=C(C(=O)NN)C=C1 REKQLYUAUXYJSZ-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HRYYAHKXNSUDFH-UHFFFAOYSA-N 5-nitrofuran-2-carbohydrazide Chemical compound NNC(=O)C1=CC=C([N+]([O-])=O)O1 HRYYAHKXNSUDFH-UHFFFAOYSA-N 0.000 description 1
- RGHDGRGJOSPDHW-UHFFFAOYSA-N 8-benzyl-1-(4-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1=CC(Cl)=CC=C1N1C2(CCN(CC=3C=CC=CC=3)CC2)C(=O)NC1 RGHDGRGJOSPDHW-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960000427 carbadox Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- YTQHSQQSLTYMSL-UHFFFAOYSA-N dodecanohydrazide Chemical compound CCCCCCCCCCCC(=O)NN YTQHSQQSLTYMSL-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- BPMVRAQIQQEBLN-OBPBNMOMSA-N methyl n-[(e)-(1-hydroxy-4-oxidoquinoxalin-4-ium-2-ylidene)methyl]iminocarbamate Chemical compound C1=CC=C2N(O)C(=C/N=NC(=O)OC)/C=[N+]([O-])C2=C1 BPMVRAQIQQEBLN-OBPBNMOMSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BYTFESSQUGDMQQ-UHFFFAOYSA-N octadecanehydrazide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NN BYTFESSQUGDMQQ-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ARKTVCBOWGYYFS-UHFFFAOYSA-N piperidine-4-carbohydrazide Chemical compound NNC(=O)C1CCNCC1 ARKTVCBOWGYYFS-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940115939 shigella sonnei Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
- C07D241/52—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Vynález se týká způsobu výroby nových derivátů chinoxalin-l,4-dioxidu obecného vzorce IThe invention relates to a process for the preparation of novel quinoxaline-1,4-dioxide derivatives of the general formula I
o ve kterémin which
R znamená alkylovou skupinu s 11 až 17 atomy uhlíku, fenylovou skupinu substituovanou hydroxyskupinou, aminoskupinou, nitroskupinou, methoxyskupinou nebo· atomem halogenu, naftylovou skupinu substituovanou hydroxyskupinou, naftylmethylskupinu, fenylethylskupinu, pyridylovou, piperidylovou, nitrofurylovou skupinu nebo α,α-difenyl-a-hydroxymethylovou skupinu.R represents an alkyl group having from 11 to 17 carbon atoms, a phenyl group substituted by hydroxy, amino, nitro, methoxy or halogen, naphthyl substituted hydroxy, naphthylmethyl, phenylethyl, pyridyl, piperidyl, nitrofuryl or α, α-diphenyl- hydroxymethyl group.
Nové sloučeniny obecného vzorce I mají baktericidní účinnost a účinek způsobující přírůstky hmotnosti jatečních zvířat.The novel compounds of the formula I have bactericidal activity and an effect causing weight gain in slaughter animals.
Z britských patentových spisů č. 1 058 047 a 1 202 170 a z amerického· patent, spisu čís. 3 433 871 je známo, že se 2-formylchinoxalin-l,4-diox.idhydrazony mohou připravovat reakcí 2-formylchinoxalin-l,4-dioxidu nebo· jeho dialkylacetalů s hydrazidy alkankarboxylových kyselin s 1 až 7 atomy uhlíku nebo s hydrazidy kyseliny benzoové, v methanolu. Tyto sloučeniny mají baktericidní účinnost a rovněž účinek způsobující přírůstky hmotnosti jatečních zvířat.British Patent Specification Nos. 1,058,047 and 1,202,170 and U.S. Pat. No. 3,433,871, it is known that 2-formylquinoxaline-1,4-dioxididrazones can be prepared by reacting 2-formylquinoxaline-1,4-dioxide or its dialkyl acetals with C1 -C7 alkanecarboxylic acid hydrazides or benzoic hydrazides. , in methanol. These compounds have bactericidal activity as well as an effect causing weight gain in slaughter animals.
Podstata výroby nových sloučenin shora uvedeného obecného vzorce I způsobem podle tohoto vynálezu spočívá v tom, že se aldehyd obecného vzorce IIThe preparation of the novel compounds of the above general formula (I) by the process according to the invention consists in the formation of the aldehyde of the general formula (II)
ve kterém Z · znamená atom kyslíku · nebo skupinu (O-alkyl)2, nechá reagovat s hydrazidem kyseliny obecného vzorce IIIin which Z · is an oxygen atom or (O-alkyl) 2, is reacted with an acid hydrazide of formula III
R—CO—NH—NHz (III) v němž R má shora uvedený význam.R = CO-NH-NH2 (III) wherein R is as defined above.
Reakce se s výhodou provádí ve vodném prostředí v přítomnosti kyseliny.The reaction is preferably carried out in an aqueous medium in the presence of an acid.
Výchozí sloučeniny, to je 2-formylchinoxalin-l,4-dioxid obecného vzorce II a jeho diacetaly, stejně jako· hydrazidy karboxylových kyselin obecného· vzorce III, se mohou připravovat o sobě známými metodami. Pro sloučeniny obecného· vzorce II viz například Ber. 84, 4771 (1951); Ž. Obšč. Chim, 25,. 161 (1955); belgický patentový spis čís. 669 353 a britský patentový spis čís. 1 058 047. Pro sloučeniny obecného· vzorce III viz J. Zabiczky: The Chemistry of Amides, kapitola 10, str. 515, Interscience Publ., 1970.The starting compounds, i.e. the 2-formylquinoxaline-1,4-dioxide of the formula II and its diacetals, as well as the carboxylic acid hydrazides of the formula III, can be prepared by methods known per se. For compounds of formula II, see, for example, Ber. 84, 4771 (1951); OF. Obšč. Chim, 25,. 161 (1955); Belgian patent no. No. 669,353 and British patent no. For compounds of Formula III, see J. Zabiczky: The Chemistry of Amides, Chapter 10, p. 515, Interscience Publ., 1970.
Při výhodném provádění způsobu podle tohoto vynálezu se postupuje tak, že se nechá reagovat 2-formylchinoxalln-l,4-dioxid obecného vzorce II s hydrazidem karboxylové kyseliny obecného vzorce III, použitým v malém přebytku, ve vodě v přítomnosti kyseliny.In a preferred embodiment of the process of the invention, 2-formylquinoxaline-1,4-dioxide of formula II is reacted with a carboxylic acid hydrazide of formula III, used in a small excess, in water in the presence of an acid.
Podle jiné výhodné formy provedení se reakce 2-formylchinoxalin-l,4-dioxiddiacetalu obecného vzorce II s hydrazidem karboxylové kyseliny obecného vzorce III provádí v kyselém reakčním· prostředí krátkým varem. Kyselá reakce prostředí · se zajistí přidáním kyseliny. Jako kyseliny se s výhodou používá minerální kyseliny, jako je kyselina chlorovodíková, sírová nebo fosforečná. Použitelná je však pro tyto účely též kyselina p-toluensulfonová.According to another preferred embodiment, the reaction of the 2-formylquinoxaline-1,4-dioxide diacetal of the formula II with the carboxylic acid hydrazide of the formula III is carried out in an acidic reaction medium by short boiling. Acidic reaction of the environment is ensured by the addition of acid. The acid used is preferably a mineral acid such as hydrochloric, sulfuric or phosphoric acid. However, p-toluenesulfonic acid is also useful for this purpose.
Jako reakčního prostředí lze používat jakéhokoliv rozpouštědla, které nereaguje s reakčními složkami nebo s produktem a je mísitelné také s kyselinou, které se používá jako katalyzátoru. Je výhodné pracovat ve vodě jakožto· reakčním prostředí.Any solvent which does not react with the reactants or the product and is also miscible with the acid used as the catalyst can be used as the reaction medium. It is preferred to work in water as the reaction medium.
Další výhodná forma provádění způsobu podle tohoto vynálezu, která je použitelná hlavně při kontinuální výrobě ve velkoprovoze k získávání nových sloučenin shora uvedeného obecného· vzorce I, spočívá v tom, že hydrazid karboxylové kyseliny používaný při reakci se nechá reagovat po> jeho vyrobení, aniž by se izoloval, tj. v reakční směsi, v · které se vyrobí, s formylchinoxalín-l,4-dioxidem· · nebo s jeho acetalem. Tím se dosahuje výhod, jako je například úspora práce a aparatur, kterých při · přerušovaném postupu pracovním nelze dosáhnout.A further preferred embodiment of the process according to the invention, which is useful mainly in continuous production in large-scale production to obtain the novel compounds of formula (I) above, is that the carboxylic acid hydrazide used in the reaction is reacted after its production without is isolated, i.e. in the reaction mixture in which it is produced, with formylquinoxaline-1,4-dioxide · or its acetal. This achieves advantages such as saving labor and equipment that cannot be achieved with intermittent work progress.
Nové sloučeniny Obecného vzorce I mají výborné baktericidní účinky při nízké jejich toxicitě. Tyto účinky byly zkoumány na · různých kmenech bakterií. Nejnižší koncentrace · MIC udávaná v mg/ml, ·která inhibuje množení testovaných bakterií, se určovala in vitro. Při testu bylo použito následujících kmenů bakterií:The novel compounds of formula (I) have excellent bactericidal activity at low toxicity. These effects have been studied in different strains of bacteria. The lowest concentration, MIC, in mg / ml, that inhibits the multiplication of test bacteria was determined in vitro. The following strains of bacteria were used in the test:
1. Pseudomonas pyocyanea 14K1. Pseudomonas pyocyanea 14K
2. Próteus vulgaris A. H.2. Proteus vulgaris A.H.
3. Bacillus subtilis ATCC 6633Bacillus subtilis ATCC 6633
4. Salmonella typhi murium4. Salmonella typhi murium
5. Shigella Sonnei5. Shigella Sonnei
6. Staphylococcus aureus DuncanStaphylococcus aureus Duncan
7. Staphylococcus aureus 209P7. Staphylococcus aureus 209P
8. Escherichia coli 0111.8. Escherichia coli 0111.
Baktericidní účinek nových sloučenin vyráběných způsobem podle tohoto vynálezu byl srovnán s účinkem známých derivátů perorálním podávání, jsou ' shrnuty v náslechinoxalin-l,4-dioxidu. Hodnoty MIC in vitro, dující tabulce:The bactericidal effect of the novel compounds produced by the process of the present invention has been compared to that of the known derivatives of oral administration, which are summarized in English-oxaline-1,4-dioxide. In vitro MIC values given in the table:
jakož i hodnoty LD50 měřeny na myších přias well as LD50 values measured in mice at
TABULKATABLE
Sloučenina LDso mg/kg Nejnižší koncentrace inhibující množení (význam R (myši, p. ' o.) testovaných bakterií (MIC) mg/mlCompound LD 50 mg / kg Lowest concentration inhibiting multiplication (meaning of R (mice, p.o.) of test bacteria (MIC) mg / ml
Z údajů uvedených v tabulce jednoznačně vyplývá, že nové sloučeniny obecného vzorce I jsou účinnější a podstatně méně toxické než známé sloučeniny obdobné struktury.The data in the table clearly show that the novel compounds of formula I are more potent and substantially less toxic than known compounds of similar structure.
Sloučeniny obecného· vzorce I mají kromě baktericidního účinku ještě účinek zvyšovat přírůstky hmotnosti u zvířat, především u prasat, takže se jejich použitím zvyšuje využití krmiv.In addition to the bactericidal effect, the compounds of the formula I have the effect of increasing the weight gain in animals, in particular pigs, so that their use increases the feed utilization.
Nové sloučeniny obecného vzorce I lze upravovat buď samotné, nebo· ve spojení s jinými farmaceutickými nebo synergickými sloučeninami, s nosiči, zřeďovadly a/nebo pomocnými látkami obvyklými ve · farmaceutickém průmyslu, na · farmaceutické preparáty.The novel compounds of formula (I) may be formulated, either alone or in conjunction with other pharmaceutical or synergistic compounds, carriers, diluents and / or excipients customary in the pharmaceutical industry, to form pharmaceutical preparations.
Způsob podle vynálezu · je blíže objasňován na podkladě následujících příkladů.The process according to the invention is explained in more detail on the basis of the following examples.
Příklad 1Example 1
2- (l‘-inaf tylacety 1) hydrazonof ormylchinoxalin-l,4-dioxid2- (1'-inaphthylacetyl) hydrazonoformylquinoxaline-1,4-dioxide
9,5 g (0,05 molu) 2-fo:rmylchínoxalin-l,4-dioxidu se rozpustí ve 100 ml vody obsahující 0,5 ml koncentrované kyseliny chlorovodíkové a k roztoku se potom přidá 10.0 g (0,05) molu hydrazidu kyseliny 1-naftyloctové. Po tříhodinovém míchání .při teplotě místnosti se suspenze filtruje a sraženina se promyje vodou a ethanolem. Tímto způsobem se získá 16,2 g (87 %) sloučeniny uvedené v nadpise, o bodu tání 246 až 247° Celsia.9.5 g (0.05 mol) of 2-fo: rmylchínoxalin-l, 4-dioxide are dissolved in 100 ml water containing 0.5 ml concentrated hydrochloric acid and the solution was then added 10.0 g (0.05) mole acid hydrazide 1-naphthylacetic. After stirring at room temperature for 3 hours, the suspension is filtered and the precipitate is washed with water and ethanol. In this way, 16.2 g (87%) of the title compound of melting point 246 DEG-247 DEG C. were obtained.
Příklad 2Example 2
2- (p-hydroxybenzoyl) hydrazonof ormylchinoxalin-l,4-dioxid ffll vodné suspenze obsahující 11,8 g (0,05 molu) 2-formylchmoxalin-l,4-dioxid-dimethylacetalu a 4 ml koncentrované kyseliny chlorovodíkové se vaří asi 10 minut, potom · se přidá 25 ml horké vodné suspenze 7,75 g (0,051 molu) hydrazidu p-hydroxybenzoové kyseliny. Reakční směs se nechá ochladit na teplotu místnosti a potom se míchá při této teplotě 3 hodiny. Oddělené krystaly se odfiltrují a promyjí vodou a ethanolem. Tímto způsobem se získá 14,95 g (92,4 %) sloučeniny uvedené v nadpise, o teplotě tání 308 °C.2- (p-hydroxybenzoyl) hydrazonoformylquinoxaline-1,4-dioxide formulated in aqueous suspension containing 11.8 g (0.05 moles) of 2-formylquinoxaline-1,4-dioxide dimethylacetal and 4 ml of concentrated hydrochloric acid is boiled for about 10 minutes 25 ml of hot aqueous suspension of 7.75 g (0.051 mol) of p-hydroxybenzoic acid hydrazide are added. The reaction mixture was allowed to cool to room temperature and then stirred at this temperature for 3 hours. The separated crystals were filtered and washed with water and ethanol. 14.95 g (92.4%) of the title compound of melting point 308 DEG C. are obtained.
Příklad 3Example 3
2- (laurinoyl) hydrazonof ormylchinoxalin-1,4-dioxíd ml vodné suspenze 11,8 g (0,05 molu) 2-formylchlnOxalin-l,4-dio-xid-dimethylacetalu a 5 ml koncentrované kyseliny forforečné se· vaří asi 10 minut a .potom se přidá 50 ml horké vodné suspenze 10,2 g (0,05 molu) hydrazidu laurové kyseliny. Reakční směs se nechá ochladit na teplotu místnosti a potom se míchá při · této· teplotě 3 hodiny. Oddělené krystaly se odfiltrují a promyjí vodou a ethanolem. Tímto způsobem se dostane 16,4 g (84,9 %) produktu uvedeného v nadpise, o· teplotě tání 233 °C.2- (laurinoyl) hydrazonoformylquinoxaline-1,4-dioxide ml of an aqueous suspension of 11.8 g (0.05 moles) of 2-formylchinoxaline-1,4-dioxide dimethylacetal and 5 ml of concentrated formic acid are boiled for about 10 minutes. 50 ml of a hot aqueous suspension of 10.2 g (0.05 mol) of lauric hydrazide are added. The reaction mixture was allowed to cool to room temperature and then stirred at this temperature for 3 hours. The separated crystals were filtered and washed with water and ethanol. This gives 16.4 g (84.9%) of the title product, m.p. 233 ° C.
Příklad 4Example 4
2- (p-aninobenzoyl) hydrazonof ormylchinoxalin-l,4-dioxid2- (p-aninobenzoyl) hydrazonoformylquinoxaline-1,4-dioxide
9,5 g (0,05 molu] 2-formylchinoxalin-l,4-dioxidu se rozpustí ve 100 ml vody, která obsahuje 0,5 kyseliny p-toluensulfonové a k roztoku se potom přidá · 7,55 g (0,05 molu) hydrazinu kyseliny p-tminobenzoové v 50 ml methanolu. Reakční směs se míchá při teplotě místnosti 3 hodiny a potom se · přefiltru9.5 g (0.05 mol) of 2-formylquinoxaline-1,4-dioxide are dissolved in 100 ml of water containing 0.5 p-toluenesulfonic acid and then 7.55 g (0.05 mol) are added. The reaction mixture is stirred at room temperature for 3 hours and then filtered.
Ί je. Odfiltrovaná sraženina se promyje vodou a ethanolem. Tímto způsobem se získá 13,1 gramu (fli.E %] sloučeniny uvudoné y пайpíše, o teplotě tání 292 °C.Ί je. The filtered precipitate was washed with water and ethanol. 13.1 g (f.E%) of the compound described above are obtained, m.p. 292 ° C.
Příklad 5Example 5
2-(nikotinoyl) hydrazonof ormyl-chinoxalin-l,4-dioxid2- (nicotinoyl) hydrazonoformyl-quinoxaline-1,4-dioxide
7,55 g (0,05 molu) ethylesteru kyseliny nikotinové se rozpustí v 60 ml ethanolu a к získanému roztoku se potom přikape 2,6 gramu (0,05 molů) 96 % hydrazinhydrátu. Reakční směs se vaří 2 hodiny a potom se к ní přikape horký roztok 9,5 g (0,05 molu) 2-formylchinoAalin-l,4-dioxidu a 1 ml koncentrované kyseliny chlorovodíkové ve 140 mililitrech methanolu. Reakční směs se nechá ochladit na teplotu místnosti, potom se míchá 2 hodiny při této teplotě. Oddělené krystaly se odfiltrují a promyjí methanolem. Tímto způsobem se získá 13,2 g (84,5 %) produktu uvedeného v nadpise, o teplotě tání 279 CC.7.55 g (0.05 mol) of ethyl nicotinate are dissolved in 60 ml of ethanol and then 2.6 g (0.05 mol) of 96% hydrazine hydrate are added dropwise. The reaction mixture was boiled for 2 hours and then a hot solution of 9.5 g (0.05 mol) of 2-formylquinoline-1,4-dioxide and 1 ml of concentrated hydrochloric acid in 140 ml of methanol was added dropwise. The reaction mixture was allowed to cool to room temperature, then stirred at this temperature for 2 hours. The separated crystals were filtered off and washed with methanol. This gives 13.2 g (84.5%) of the title product, mp 279 C C.
Příklad 6Example 6
2-(isonikotinoyl) hydrazonof ormylchinoxalin-l,4-dioxid2- (isonicotinoyl) hydrazonoformylquinoxaline-1,4-dioxide
Když se nechá reagovat způsobem popsaným v příkladu 2 11,8 g (0,05 molu) 2-formylchinoxalin-l,4-dioxid-dimethylacetalu a 6,85 g (0,05 molu) hydrazidu kyseliny isonikotinové, získá se 14,4 g (93,2 %) sloučeniny uvedené v nadpise, o teplotě tání 268° Celsia.When reacted as described in Example 2, 11.8 g (0.05 mol) of 2-formylquinoxaline-1,4-dioxide dimethylacetal and 6.85 g (0.05 mol) of isonicotinic hydrazide gave 14.4 g. g (93.2%) of the title compound, m.p. 268 ° C.
Příklad 7Example 7
2-(p-chlorbenzoyl) hydrazonof ormylchinoxalin-l,4-dioxid2- (p-chlorobenzoyl) hydrazonoformylquinoxaline-1,4-dioxide
16,1 g (95 %) látky uvedené v nadpise, o teplotě tání 274 CC, se získá, když se nechá reagovat 11,8 g (0,05 molu) 2-formylchinoxalin-l,4-dioxid-dimethylacetalu a 8,5 g (0,05 molu) hydrazidu kyseliny p-chlorbenzoové způsobem popsaným v příkladě 1.16.1 g (95%) of the title compound, m.p. 274 DEG C., is obtained by reacting 11.8 g (0.05 mol) of 2-formylquinoxaline-1,4-dioxide dimethylacetal and 8. 1.5 g (0.05 mol) of p-chlorobenzoic hydrazide as described in Example 1.
Příklad 8Example 8
2- (3‘-nitrobenzoyl) hydrazonof ormylchinoxalin-l,4-dioxid2- (3‘-Nitrobenzoyl) hydrazonoformylquinoxaline-1,4-dioxide
16,15 g (91,6 %) látky uvedené v nadpise, o teplotě tání 290 °C, se získá, když se nechá reagovat 9,5 g (0,05 molu) 2-formylchinoxalin-l,4-dioxidu a 9,05 g (0,05 molu) hydrazidu kyseliny 3-nitrobenzoové způsobem popsaným v příkladě 1.16.15 g (91.6%) of the title compound, m.p. 290 DEG C., is obtained by reacting 9.5 g (0.05 mol) of 2-formylquinoxaline-1,4-dioxide and 9 g. 0.05 g (0.05 mol) of 3-nitrobenzoic acid hydrazide as described in Example 1.
Příklad 9Example 9
2- (5<-nitro-2<-f uranoyl) hydrazonof ormylchinoxalin-l,4-dioixd2- (5 <nitro-2 <-f uranoyl) hydrazonof ormylchinoxalin-l, 4-dioixd
Sloučenina uvedená v nadpise o teplotě tání 265 °C se ve výtěžku 82,6 % získá poříkladu 2 z 2-formylchinoxalin-l,4-dioxid-dimethylacetalu a hyd razidu kyseliny 5-nitro-furan-2-karboxylové.The title compound, m.p. 265 DEG C., was obtained in a yield of 82.6%, for example, 2 of 2-formylquinoxaline-1,4-dioxide dimethylacetal and 5-nitro-furan-2-carboxylic acid hydrazide.
Příklad 10Example 10
2- (/З-f enylpr opionyl ] hy drazonof ormylchinoxalin-l,4-dioxid2- (η-Phenylpropionyl) hydrazonoformylquinoxaline-1,4-dioxide
Když se nechá reagovat 2-formylchinoxalin-l,4-dioxid-dimethylacetal a hydrazid kyseliny 3-fenylpropionové jako je popsáno v příkladě 2, dostane se sloučenina uvedená v nadpise, o teplotě tání 241CC, ve výtěžku 90,5 %.When 2-formylquinoxaline-1,4-dioxide dimethylacetal and 3-phenylpropionic acid hydrazide were reacted as described in Example 2, the title compound, m.p. 241 DEG C., was obtained in a yield of 90.5%.
Příklad 11Example 11
2- [stearoyl ) hydrazonof ormylchinoxalin-l,4-dioxid2- [stearoyl] hydrazonoformylquinoxaline-1,4-dioxide
2-formylchino <alin-l,4-dioxid-dimethylacetal se nechá reagovat s hydrazidem kyseliny stearové způsobem popsaným v příkladu 2 a získá se sloučenina uvedená v nadpise o teplotě tání 233 °C, ve výtěžku 74,2 °/o.2-Formylquinoline-1,4-dioxide dimethylacetal was treated with stearic hydrazide as described in Example 2 to give the title compound, mp 233 ° C, yield 74.2%.
Příklad 12Example 12
2- (anisoyl) hydrazonof ormylchinoxalin-1,4-dioxid2- (anisoyl) hydrazonoformylquinoxaline-1,4-dioxide
2-formylchinoxalin-l,4-dioxid-dimethylacetal se nechá reagovat s hydrazidem kyseliny anisové způsobem popsaným v příkladu 2 a získá se sloučenina uvedená v nadpise o teplotě tání 260 CC, ve výtěžku 79 procent.2-Formylquinoxaline-1,4-dioxide dimethylacetal was reacted with anisic hydrazide as described in Example 2 to give the title compound, m.p. 260 DEG C., 79% yield.
Příklad 13Example 13
2- (piperidin-2‘-karbonyl )hydrazonoformylchinoxalin-l,4-dioxid2- (piperidine-2'-carbonyl) hydrazonoformylquinoxaline-1,4-dioxide
Způsobem popsaným v příkladu 1 se získá sloučenina uvedená v nadpise, o teplotě tání 186 °C, ve výtěžku 75 %, reakcí 2-formylchinoxalin-l,4-dioxidu s hydrazidem kyseliny piperidin-4-karboxylové.Following the procedure described in Example 1, the title compound, m.p. 186 DEG C., 75% yield, was reacted with 2-formylquinoxaline-1,4-dioxide with piperidine-4-carboxylic acid hydrazide.
Příklad 14Example 14
2- (2‘-hydroxy-3ť-naftoyl)hydrazonoformylchinoxalin-l,4-dioxid2- (2'-hydroxy-3'-naphthoyl) hydrazonoformylchinoxalin-l, 4-dioxide
Když se nechá reagovat 2-formylchinoxalin-l,4-dioxid-dimethylacetal s hydrazidem kyseliny 2-hydroxy-3-naftoové jako je popsáno v příkladě 2, dostane se sloučenina uvedená v nadpise, o teplotě tání 260 °С, ve výtěžku 97,3 °/o.When 2-formylquinoxaline-1,4-dioxide dimethylacetal is reacted with 2-hydroxy-3-naphthoic acid hydrazide as described in Example 2, the title compound is obtained, m.p. 260 ° C, yield 97, m.p. 0 ° / o.
Příklad 15Example 15
2-(a,a-difenyl-a-hydroxy)acetylhydrazonoformylchinoxalin-l,4-dloxid2- (α, α-diphenyl-α-hydroxy) acetylhydrazonoformylquinoxaline-1,4-dloxide
2327G32327G3
Když se nechá reagovat 2-formylchinoxalin-l,4-dioxid-dimethylacetyl a hydrazid kyseliny benzoové jako je v příkladěWhen 2-formylquinoxaline-1,4-dioxide dimethylacetyl and benzoic hydrazide are reacted as in the example
2, dostane se sloučenina uvedená v nadpise, o teplotě tání ' 262 až 263 %C, ve výtěžku 94,9 %.2 to give the title compound, m.p. 262-263% C, yield 94.9%.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUEE2278A HU169299B (en) | 1974-11-21 | 1974-11-21 |
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| CS232703B2 true CS232703B2 (en) | 1985-02-14 |
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| CS757830A CS232703B2 (en) | 1974-11-21 | 1975-11-19 | Production method of new quinoxaline-1,4-dioxide derivatives |
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| JP (1) | JPS6049634B2 (en) |
| AT (1) | AT344702B (en) |
| BE (1) | BE835763A (en) |
| CH (1) | CH623042A5 (en) |
| CS (1) | CS232703B2 (en) |
| DD (1) | DD123604A5 (en) |
| DE (1) | DE2552289C2 (en) |
| DK (1) | DK138389B (en) |
| FI (1) | FI61887C (en) |
| FR (1) | FR2291756A1 (en) |
| GB (1) | GB1479239A (en) |
| HU (1) | HU169299B (en) |
| IL (1) | IL48463A (en) |
| IN (1) | IN140110B (en) |
| NL (1) | NL7513446A (en) |
| PL (1) | PL96412B1 (en) |
| SE (2) | SE423095B (en) |
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| YU (1) | YU39953B (en) |
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| IT1058490B (en) * | 1976-03-18 | 1982-04-10 | Ind Chimica Prodotti Francis S | MANUFACTURING PROCEDURE OF ALCHIL 3 2 KINOXALYLMETHYLEN CARBATATE 1.4 DIOXIDE |
| HU184772B (en) * | 1980-05-23 | 1984-10-29 | Egyt Gyogyszervegyeszeti Gyar | Process for preparing quinoxaline-1,4-dioxide derivatives |
| HU184825B (en) * | 1980-09-12 | 1984-10-29 | Egyt Gyogyszervegyeszeti Gyar | Process for preparing new 2-hydroxy-methyl-quinoxaline-1,4-dioxide derivatives |
| AU2314488A (en) * | 1987-07-31 | 1989-03-01 | Upjohn Company, The | Anthelmintic acylhydrazones, method of use and compositions |
| US5049561A (en) * | 1987-07-31 | 1991-09-17 | The Upjohn Company | Anthelmintic acylhydrazones, method of use and compositions |
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| FR1469485A (en) * | 1964-09-16 | 1967-02-17 | Pfizer & Co C | Process for the preparation of a new series of schiff bases |
| US3371090A (en) * | 1964-09-16 | 1968-02-27 | Pfizer & Co C | Novel antibacterial agents |
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1975
- 1975-11-11 IL IL48463A patent/IL48463A/en unknown
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- 1975-11-14 IN IN2177/CAL/75A patent/IN140110B/en unknown
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- 1975-11-17 AT AT872275A patent/AT344702B/en not_active IP Right Cessation
- 1975-11-18 NL NL7513446A patent/NL7513446A/en not_active Application Discontinuation
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- 1975-11-18 FR FR7535184A patent/FR2291756A1/en active Granted
- 1975-11-19 CS CS757830A patent/CS232703B2/en unknown
- 1975-11-19 SU SU752189810A patent/SU612628A3/en active
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- 1975-11-20 BE BE162030A patent/BE835763A/en not_active IP Right Cessation
- 1975-11-20 PL PL1975184870A patent/PL96412B1/en unknown
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Also Published As
| Publication number | Publication date |
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| YU39953B (en) | 1985-06-30 |
| DE2552289C2 (en) | 1986-05-07 |
| FR2291756B1 (en) | 1978-11-10 |
| DK138389B (en) | 1978-08-28 |
| NL7513446A (en) | 1976-05-25 |
| SE423387B (en) | 1982-05-03 |
| BE835763A (en) | 1976-03-16 |
| SU612628A3 (en) | 1978-06-25 |
| AT344702B (en) | 1977-12-15 |
| DK518275A (en) | 1976-05-22 |
| JPS5175082A (en) | 1976-06-29 |
| JPS6049634B2 (en) | 1985-11-02 |
| DE2552289A1 (en) | 1976-05-26 |
| FI753225A7 (en) | 1976-05-22 |
| SE7512857L (en) | 1976-05-24 |
| YU294275A (en) | 1982-06-30 |
| FI61887C (en) | 1982-10-11 |
| FR2291756A1 (en) | 1976-06-18 |
| DK138389C (en) | 1979-02-05 |
| CH623042A5 (en) | 1981-05-15 |
| DD123604A5 (en) | 1977-01-05 |
| HU169299B (en) | 1976-11-28 |
| FI61887B (en) | 1982-06-30 |
| IN140110B (en) | 1976-09-18 |
| IL48463A0 (en) | 1976-01-30 |
| SE423095B (en) | 1982-04-13 |
| IL48463A (en) | 1978-10-31 |
| ATA872275A (en) | 1977-12-15 |
| SE7900389L (en) | 1979-01-16 |
| GB1479239A (en) | 1977-07-06 |
| PL96412B1 (en) | 1977-12-31 |
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