NO159586B - PROCEDURE FOR ANAEROBIC WASTE CLEANING. - Google Patents
PROCEDURE FOR ANAEROBIC WASTE CLEANING. Download PDFInfo
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- NO159586B NO159586B NO853600A NO853600A NO159586B NO 159586 B NO159586 B NO 159586B NO 853600 A NO853600 A NO 853600A NO 853600 A NO853600 A NO 853600A NO 159586 B NO159586 B NO 159586B
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- carbon atoms
- group
- compounds
- alkyl
- aminoadamantane
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- 238000000034 method Methods 0.000 title claims description 13
- 238000004140 cleaning Methods 0.000 title 1
- 239000002699 waste material Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 44
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- -1 carboxymethyl- Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical class C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
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- 239000004480 active ingredient Substances 0.000 description 8
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- 230000000694 effects Effects 0.000 description 6
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- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 4
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
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- 241000699670 Mus sp. Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- XDIYNQZUNSSENW-UUBOPVPUSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XDIYNQZUNSSENW-UUBOPVPUSA-N 0.000 description 1
- VQHPRVYDKRESCL-UHFFFAOYSA-N 1-bromoadamantane Chemical compound C1C(C2)CC3CC2CC1(Br)C3 VQHPRVYDKRESCL-UHFFFAOYSA-N 0.000 description 1
- CYDWIRQXNVCQBX-UHFFFAOYSA-N 2-(1-adamantylamino)ethanol Chemical compound C1C(C2)CC3CC2CC1(NCCO)C3 CYDWIRQXNVCQBX-UHFFFAOYSA-N 0.000 description 1
- 240000002470 Amphicarpaea bracteata Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 240000000359 Triticum dicoccon Species 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
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- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XVIYCJDWYLJQBG-UHFFFAOYSA-N acetic acid;adamantane Chemical compound CC(O)=O.C1C(C2)CC3CC1CC2C3 XVIYCJDWYLJQBG-UHFFFAOYSA-N 0.000 description 1
- UPWLURAENVJIJL-UHFFFAOYSA-N adamantane;hydrochloride Chemical compound Cl.C1C(C2)CC3CC1CC2C3 UPWLURAENVJIJL-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
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- 239000012736 aqueous medium Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960000892 attapulgite Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
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- 238000009713 electroplating Methods 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- NZOLSRPWNVZXTK-UHFFFAOYSA-N n-methyladamantan-1-amine Chemical compound C1C(C2)CC3CC2CC1(NC)C3 NZOLSRPWNVZXTK-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Purification Treatments By Anaerobic Or Anaerobic And Aerobic Bacteria Or Animals (AREA)
- Separation Of Suspended Particles By Flocculating Agents (AREA)
- External Artificial Organs (AREA)
Description
Fremgangsmåte til fremstilling av terapeutisk aktive 1-aminoadamantanderivater. Process for the preparation of therapeutically active 1-aminoadamantane derivatives.
Oppfinnelsen angår en fremgangsmåte til fremstilling av 1-aminoadamantan-deriva-ter, samt av sådanne forbindelsers syreaddisjonssalter. The invention relates to a method for the production of 1-aminoadamantane derivatives, as well as the acid addition salts of such compounds.
Adamantan kan også betegnes som tri-cyclo-(3,3,l,l<3,7>)-decan. Fremstilling av denne forbindelse er beskrevet i U.S. patent nr. 2 937 211. Adamantane can also be referred to as tri-cyclo-(3,3,1,1<3,7>)-decane. Preparation of this compound is described in U.S. Pat. patent No. 2,937,211.
Det har vist seg at en rekke adamantanderivater har ytterst verdifulle terapeutiske egenskaper, så at de er fordelaktige til anvendelse i farmasien. Det er funnet at de forbindelser som fåes ved fremgangsmåten ifølge oppfinnelsen er særlig effektive til behandling av virusinfeksjoner og lignende tilstander som er skadelige for helsen og velbefindenet. It has been found that a number of adamantane derivatives have extremely valuable therapeutic properties, so that they are advantageous for use in pharmacy. It has been found that the compounds obtained by the method according to the invention are particularly effective for the treatment of viral infections and similar conditions which are harmful to health and well-being.
Disse forbindelser er funnet å være an-vendbare også som antioxydasjonsmidler. These compounds have been found to be usable also as antioxidants.
De adamantanderivater som fremstilles ved fremgangsmåten ifølge oppfinnelsen tilsvarer følgende generelle formel: i hvilken R<1> betegner hydrogen, en alkylgruppe med 1—12 carbonatomer, fortrinnsvis 1—4 carbonatomer, en monosubstituert alkylgruppe med 1—4 carbonatomer i hvilken substituenten er halogen, en hydroxylgruppe, en ålkoxygruppe med 1—3 carbonatomer, en aminogruppe, en alkylaminogruppe med 1—2 carbonatomer, en dialkylaminogruppe hvor hver alkylgruppe inneholder 1—2 carbonatomer, eller en hydroxyalkoxyalkylgruppe, hvor alkoxydelen har 1—3 carbonatomer, mens alkyldelen inneholder 1—4 carbonatomer, og Z betegner en alkylgruppe med 1—12 carbonatomer, en monosubstituert alkylgruppe med 1—4 carbonatomer i hvilken substituenten er halogen, en hydroxylgruppe, en ålkoxygruppe med 1—3 carbonatomer, en aminogruppe, en alkylaminogruppe med 1—2 carbonatomer, en dialkylaminogruppe i hvilken hver alkylgruppe inneholder 1—2 carbonatomer, eller en hydroxyalkoxyalkylgruppe i hvilken alkoxydelen inneholder 1—3 carbonatomer, mens alkyldelen inneholder 1—4 carbonatomer, en carboxymethyl-, mehoxycarbonyl-methyl- eller ethoxycarbonylmethylgruppe, idet gruppen — NR<*>Z inneholder høyst 12 The adamantane derivatives produced by the method according to the invention correspond to the following general formula: in which R<1> denotes hydrogen, an alkyl group with 1-12 carbon atoms, preferably 1-4 carbon atoms, a monosubstituted alkyl group with 1-4 carbon atoms in which the substituent is halogen, a hydroxyl group, an alkoxy group with 1-3 carbon atoms, an amino group, an alkylamino group with 1-2 carbon atoms, a dialkylamino group where each alkyl group contains 1-2 carbon atoms, or a hydroxyalkylalkyl group, where the alkoxy part has 1-3 carbon atoms, while the alkyl part contains 1- 4 carbon atoms, and Z denotes an alkyl group with 1-12 carbon atoms, a monosubstituted alkyl group with 1-4 carbon atoms in which the substituent is halogen, a hydroxyl group, an alkoxy group with 1-3 carbon atoms, an amino group, an alkylamino group with 1-2 carbon atoms, a dialkylamino group in which each alkyl group contains 1-2 carbon atoms, or a hydroxyalkylalkyl group in which the alkoxy part contains 1-3 carbon atoms, while the alkyl part contains 1-4 carbon atoms, a carboxymethyl-, methoxycarbonyl-methyl- or ethoxycarbonylmethyl group, the group — NR<*>Z containing at most 12
carbonatomer. carbon atoms.
Oppfinnelsen omfatter også fremstilling av syreaddisjonssalter av forbindelser med den ovenfor angitte generelle formel (I). The invention also encompasses the preparation of acid addition salts of compounds with the above-mentioned general formula (I).
Fremgangsmåten ifølge oppfinnelsen er karakterisert ved at man mono- eller dialkylerer usubstituert 1-aminoadamantan ved omsetning med et passende alkylhalogenid eller et passende alkylenoxyd og derefter — om ønskes — overfører den erholdte forbindelse til et syreaddisjonssalt. The method according to the invention is characterized by mono- or dialkylating unsubstituted 1-aminoadamantane by reaction with a suitable alkyl halide or a suitable alkylene oxide and then - if desired - transferring the obtained compound to an acid addition salt.
Inneholder alkyleringsmidlet en reaktiv komponent, utføres omsetningen med det u-substituerte 1-aminoadamantan i en sterk syre, f. eks. svovelsyre, hvorved den reaktive funksjon protoneres og således beskyttes mot å reagere med 1-aminoadamantanet. If the alkylating agent contains a reactive component, the reaction is carried out with the unsubstituted 1-aminoadamantane in a strong acid, e.g. sulfuric acid, whereby the reactive function is protonated and thus protected from reacting with 1-aminoadamantane.
Det vil forståes at forbindelsene med ovenstående generelle formel (I) danner salter med ikke-toksiske syrer da de inneholder en basisk amingruppe og fremstilling av sådanne salter faller innenfor oppfinnelsens ramme. Slike salter forøker forbindelsenes anvende-lighet i farmasien. Eksempler på sådanne salter er hydrokloridet, hydrobromidet, sulfatet, fosfatet, acetatet, lactatet, succinatet, propio-natet, tartratet, citratet og bicarbonatet. Blant disse salter foretrekkes hydrokloridet og acetatet. It will be understood that the compounds with the above general formula (I) form salts with non-toxic acids as they contain a basic amine group and the production of such salts falls within the scope of the invention. Such salts increase the compounds' applicability in pharmacy. Examples of such salts are the hydrochloride, hydrobromide, sulphate, phosphate, acetate, lactate, succinate, propionate, tartrate, citrate and bicarbonate. Among these salts, the hydrochloride and the acetate are preferred.
Det fremgår av det ovenstående at oppfinnelsen omfatter l-(N-substituert amino)-adamantaner. Oppfinnelsen omfatter også blandinger av sådanne forbindelser, uansett' om de fremstilles som sådanne ved syntese eller fremkommer ved • sammenblanding efter fremstillingen. It appears from the above that the invention comprises 1-(N-substituted amino)-adamantanes. The invention also covers mixtures of such compounds, regardless of whether they are produced as such by synthesis or appear by mixing together after production.
1-aminoadamantan som er en kjent forbindelse kan fremstilles ved hydrolyse ved høye temperaturer av 1-acetamidoamanantan som på sin side bekvemt kan fremstilles fra 1-bromadamantan, acetonitril og svovelsyre. 1-Aminoadamantane, which is a known compound, can be prepared by hydrolysis at high temperatures of 1-acetamidoamamantane, which in turn can conveniently be prepared from 1-bromoadamantane, acetonitrile and sulfuric acid.
Fremstillingen av saltene av forbindelser med den foran angitte generelle formel (I) kan utføres ved å oppløse vedkommende forbindelse i vann eller I et annet egnet oppløs-ningsmiddel som inneholder en eller flere ekvivalenter av en syre. Man kan f. eks. omrøre forbindelsen! med en liten mengde vann og tilsette en molar ekvivalent mengde konsentrert saltsyre. Det erholdte materiale kan inndampes i vakuum ved moderate temperaturer, hvorved der dannes forbindelsens hydroklorid i form av et fast stoff. The preparation of the salts of compounds with the above general formula (I) can be carried out by dissolving the compound in question in water or in another suitable solvent containing one or more equivalents of an acid. One can e.g. stir the connection! with a small amount of water and add a molar equivalent amount of concentrated hydrochloric acid. The material obtained can be evaporated in a vacuum at moderate temperatures, whereby the hydrochloride of the compound is formed in the form of a solid.
Til ytterligere illustrasjon kan nevnes at de ovenfor nevnte salter kan fremstilles i en oppløsning av et organisk oppløsningsmiddel. Man kan f. eks. oppløse l-(methylamino)-adamantan i ethanol og tilsette en molar ekvivalent mengde eddiksyre oppløst i alkohol. Det herved erholdte l-(methylamino)-ada-mantanacetat kan isoleres ved inndampning av oppløsningen i vakuum ved moderate temperaturer. For further illustration, it can be mentioned that the above-mentioned salts can be prepared in a solution of an organic solvent. One can e.g. dissolve l-(methylamino)-adamantane in ethanol and add a molar equivalent amount of acetic acid dissolved in alcohol. The 1-(methylamino)-adamantane acetate thus obtained can be isolated by evaporating the solution in vacuum at moderate temperatures.
Eksempler på forskjellige salter som kan fremstilles under anvendelse av passende syrer på den ovenfor beskrevne konvensjonelle måte er følgende: 1-dimethylamirioadamantan-hydroklorid 1-methylaminoadamantan-succinat 1-diethylaminoadamantan-citrat 1-dodecylaminoadamantan-tartrat 1-octylaminoadamantan-lactat Examples of various salts which can be prepared using suitable acids in the conventional manner described above are the following: 1-dimethylamirioadamantane hydrochloride 1-methylaminoadamantane succinate 1-diethylaminoadamantane citrate 1-dodecylaminoadamantane tartrate 1-octylaminoadamantane lactate
1- (dimethylaminopropylamino) - 1-(dimethylaminopropylamino)-
adamantan-acetat adamantane acetate
1- (dimethylaminoethylamino) - 1-(dimethylaminoethylamino)-
adamantan-hydroklorid adamantane hydrochloride
1- (2-hydroxyethyl) -aminoadamantan-propionat 1-(2-hydroxyethyl)-aminoadamantane propionate
1-hydroxyethoxyethylaminoadamantan-sulfat 1-Hydroxyethoxyethylaminoadamantane sulfate
1- (3-hydroxypropyl) -aminoadamantan-bikarbonat 1-(3-hydroxypropyl)-aminoadamantane bicarbonate
l-(dimethylaminopropylamino-adaman-mantan-diacetat 1-(dimethylaminopropylamino-adamane-manthane-diacetate).
1- (2-klorethyl) -aminoadamantan-hydroklorid l-(4-methoxybutyl)-aminoadamantan-acetat. 1-(2-Chloroethyl)-aminoadamantane hydrochloride 1-(4-methoxybutyl)-aminoadamantane acetate.
De ovenfor nevnte salter kan også anvendes som modifiseringsmidler i elektroplet-teringsbad. The above-mentioned salts can also be used as modifiers in electroplating baths.
De forbindelser som tilsvarer den foran angitte generelle formel I utgjør en særlig klasse med uventede fordelaktige egenskaper. Som eksempel på dette kan nevnes deres gunstige forhold med hensyn til giftighet, særlig ved forholdsvis høye doser. Absorp-sjonshastigheter, lett håndtering, stabilitet og forenlighet med farmasøytiske tilsetnings-midler er også meget gode hos mange av disse forbindelser. Forbindelsenes damptrykk gjør dem godt egnet til anvendelse ved f. eks. behandling av nesen, herunder påføring ved sprøytning og i dampform. The compounds corresponding to the above-mentioned general formula I constitute a special class with unexpected advantageous properties. As an example of this, their favorable relationship with regard to toxicity can be mentioned, especially at relatively high doses. Absorption rates, easy handling, stability and compatibility with pharmaceutical additives are also very good with many of these compounds. The vapor pressure of the compounds makes them well suited for use in e.g. treatment of the nose, including application by spraying and in vapor form.
De forbindelser som inneholder hydroxyl-eller alkoxysubstituenter eller begge deler har vist seg å være særlig anvendelige på grunn av i fremragende grad økede hydrofile egenskaper. The compounds containing hydroxyl or alkoxy substituents or both have been found to be particularly useful because of their remarkably increased hydrophilic properties.
Blant forbindelsene med den generelle formel (I) er dialkylaminoforbindelsene særlig fordelaktige og foretrekkes især på grunn av at de er meget aktive og i bemerkelses-verdig grad ikke gir uønskede bivirkninger, hva der er påvist ved forsøk. Monoethylamino-og høyere molekylære monoalkylaminoforbindelser gir likeledes vesentlige fordeler i denne henseende. Among the compounds of the general formula (I), the dialkylamino compounds are particularly advantageous and are especially preferred due to the fact that they are very active and to a remarkable extent do not produce unwanted side effects, which has been proven in experiments. Monoethylamino and higher molecular weight monoalkylamino compounds likewise provide significant advantages in this respect.
Mens de foran nevnte fordeler ved de ikke-substituerte monoalkylaminoforbindelser og de ikke-substituerte dialkylaminoforbindelser gjør disse forbindelser foretrukne, har andre av de forbindelser som fremstilles ved fremgangsmåten ifølge oppfinnelsen særlig nyttige kombinasjoner av egenskaper under visse omstendigheter. Substituerte alkylami-no- og substituerte dialkylaminoforbindelser gir f. eks. fordeler ved opparbeidelse til preparater, som f. eks. en lett oppløselighet i vann, hva der særlig er tilfelle med de hydroxy- og alkoxy-substituerte forbindelser. Blant de forbindelser som fremstilles ved foreliggende fremgangsmåte foretrekkes særlig saltene på grunn av deres fremragende kombinasjon av egenskaper, og spesielt hydrokloridet og acetatet av følgende forbindelser: 1-methylaminoadamantan While the aforementioned advantages of the unsubstituted monoalkylamino compounds and the unsubstituted dialkylamino compounds make these compounds preferred, other of the compounds produced by the method according to the invention have particularly useful combinations of properties under certain circumstances. Substituted alkylamino and substituted dialkylamino compounds give e.g. advantages when processed into preparations, such as e.g. an easy solubility in water, which is particularly the case with the hydroxy- and alkoxy-substituted compounds. Among the compounds produced by the present process, the salts are particularly preferred because of their outstanding combination of properties, and in particular the hydrochloride and the acetate of the following compounds: 1-methylaminoadamantane
1-ethylaminoadamantan 1-dimethylaminoadamantan Forbindelsene med den generelle formel (I) kan ved behandling av virusinfeksjoner anvendes på en hvilkensomhelst måte, som skaffer kontakt mellom den aktive forbindelse og det sted hvor virusinfeksjonen be-finner seg i legemet. Behandlingen kan utfø-res før eller efter infeksjonens utbredelse. Anvendelsen kan skje parenteralt, dvs. sub-kutant, intravenøst, intramuskulært eller in-traperitonalt. Forbindelsene er også effektive ved oral anvendelse evenetuelt i forbindelse med parenteral tilførsel. Da de er særlig effektive mot infeksjoner i åndedrettsorganene, f. eks. virusinfluensa og viruspneumoni, hvorved de kan tilføres i dampform eller i for-støvet tilstand gjennom munnen eller passa-sjene i nesen. 1-ethylaminoadamantane 1-dimethylaminoadamantane The compounds of the general formula (I) can be used in the treatment of viral infections in any way, which provides contact between the active compound and the place where the viral infection is in the body. The treatment can be carried out before or after the spread of the infection. The application can take place parenterally, i.e. subcutaneously, intravenously, intramuscularly or intraperitoneally. The compounds are also effective when used orally, possibly in connection with parenteral administration. As they are particularly effective against infections in the respiratory organs, e.g. viral influenza and viral pneumonia, whereby they can be administered in vapor form or in atomized state through the mouth or the passages in the nose.
Forbindelsene er videre verdifulle til pro-fylaktisk behandling mot infeksjoner, samt til annen terapeutisk behandling. The compounds are also valuable for prophylactic treatment against infections, as well as for other therapeutic treatment.
Den anvendte dose er avhengig av den virus som bekjempes, pasientens alder, helse-tilstand og vekt, av infeksjonsgraden, arten av en eventuell samtidig behandling, behand-lingens hyppighet og den ønskede virknings natur. I alminnelighet anvendes en daglig dose av den aktive forbindelse fra ca. 1 til 200 mg pr. kg legemsvekt, mens der også kan anvendes mindre mengder, f. eks. 0,5 mg. En mengde på 1—50, fortrinnsvis 1—20 mg pr. kg legemsvekt pr. døgn fordelt på én eller flere doser pr. døgn, er i alminnelighet effektiv til oppnåelse av de ønskede resul-tater. The dose used depends on the virus being combated, the patient's age, state of health and weight, the degree of infection, the nature of any simultaneous treatment, the frequency of the treatment and the nature of the desired effect. In general, a daily dose of the active compound from approx. 1 to 200 mg per kg body weight, while smaller amounts can also be used, e.g. 0.5 mg. An amount of 1-50, preferably 1-20 mg per kg body weight per day divided into one or more doses per day, is generally effective in achieving the desired results.
Forbindelsene med den .generelle formel (I) kan opparbeides til preparater som tabletter, kapsler, pulvere eller oppløsninger, suspensjoner eller miksturer for oral anvendelse eller oppløsninger til parenteralt bruk og, — i visse tilfelle — suspensjoner til parenteral anvendelse med unntagelse av intra-venøs tilførsel. I sådanne preparater er den aktive bestanddel i alminnelighet alltid til-stede i en mengde på minst 0,0001 vekt% beregnet på preparatets totalvekt og høyst i en mengde på 99 vekt%. The compounds of the general formula (I) can be prepared into preparations such as tablets, capsules, powders or solutions, suspensions or mixtures for oral use or solutions for parenteral use and, — in certain cases — suspensions for parenteral use with the exception of intravenous supply. In such preparations, the active ingredient is generally always present in an amount of at least 0.0001% by weight calculated on the total weight of the preparation and at most in an amount of 99% by weight.
Foruten forbindelser med den generelle formel (I) som aktiv bestanddel kan preparater til behandling av virusinfeksjoner inneholde faste eller flytende bærere eller for-tynningsmidler av den art som anvendes i farmasien. In addition to compounds with the general formula (I) as active ingredient, preparations for the treatment of viral infections may contain solid or liquid carriers or diluents of the kind used in pharmacy.
I en utførelsesform for farmasøytiske preparater inneholdende forbindelsene er det In one embodiment of pharmaceutical preparations containing the compounds it is
faste bærestoff en kapsel, som kan være av den alminnelige gelatintype. I en annen ut-førelsesform er den aktive bestanddel pres-set til tabletter med eller uten tilsetnings-stoffer. Den aktive bestanddel kan som ovenfor nevnt også anvendes i form av pulvere. Slike kapsler, tabletter og pulvere inneholder fortrinnsvis fra • ca. 5 til ca. 500 mg aktiv bestanddel, idet det foretrekkes å anvende en mengde fra 25 til 250 mg. Den aktive bestanddel utgjør i alminnelighet fra 5 til 95 vekt% av preparatenes vekt. solid carrier a capsule, which can be of the ordinary gelatin type. In another embodiment, the active ingredient is pressed into tablets with or without additives. As mentioned above, the active ingredient can also be used in the form of powders. Such capsules, tablets and powders preferably contain from • approx. 5 to approx. 500 mg of active ingredient, it being preferred to use an amount of from 25 to 250 mg. The active ingredient generally makes up from 5 to 95% by weight of the weight of the preparations.
De farmasøytiske bærere kan som tidli-gere nevnt være en steril væske, f. eks. vann eller en olje, deriblant væsker av mineralsk, animalsk, vegetabilsk eller syntetisk opprin-nelse, som f. eks. jordnøttolje, soyabønneolje, mineraloljer og torskeleveroljer. I alminnelighet er vann, en saltoppløsning og vandige dextrose- (glucose) og lignende sukkeroppløs-ninger å foretrekke som flytende bærestoffer, særlig til injiserbare oppløsninger. Sterile injiserbare oppløsninger inneholder i alminnelighet fra 0,5 til 25 vekt% av den aktive bestanddel, fortrinnsvis fra ca. 5 til 10 vekt%. As previously mentioned, the pharmaceutical carriers can be a sterile liquid, e.g. water or an oil, including liquids of mineral, animal, vegetable or synthetic origin, such as e.g. peanut oil, soybean oil, mineral oils and cod liver oils. In general, water, a salt solution and aqueous dextrose (glucose) and similar sugar solutions are preferred as liquid carriers, especially for injectable solutions. Sterile injectable solutions generally contain from 0.5 to 25% by weight of the active ingredient, preferably from approx. 5 to 10% by weight.
Som ovenfor nevnt kan man til oral anvendelse bruke en egnet suspensjon eller en sirup, i hvilken den aktive bestanddel i alminnelighet utgjør ca. 0,5—10 vekt%, fortrinnsvis fra 2 til 5 vekt%.' Den farmasøy-tiske bærer i et slikt preparat kan være et vandig medium, f. eks. et aromatisk vann, en sirup eller slimstoffer som anvendes i farmasien. As mentioned above, a suitable suspension or syrup can be used for oral use, in which the active ingredient generally makes up approx. 0.5-10% by weight, preferably from 2 to 5% by weight. The pharmaceutical carrier in such a preparation can be an aqueous medium, e.g. an aromatic water, a syrup or mucilage substances used in pharmacy.
Egnede farmasøytiske bærere er beskrevet i «The Pharmacological Basis of Thera-peutics» av L. G. Goodman og A. Gilman, som er en velkjent håndbok på dette om-råde. Suitable pharmaceutical carriers are described in "The Pharmacological Basis of Therapeutics" by L. G. Goodman and A. Gilman, which is a well-known handbook in this field.
De forbindelser som fremstilles ved fremgangsmåten ifølge oppfinnelsen er særlig effektive mot svineinfluensa. Denne infeksjon kan bekjempes ved å innblande en av forbindelsene i det angrepne dyrs for. For de fleste formål anvendes forbindelsene i slik mengde at man får fra 0,0001 til 0,1 vekt% aktiv forbindelse beregnet på den totale vekt-mengde fortært for, fortrinnsvis fra 0,001 til 0,02 vekt%. The compounds produced by the method according to the invention are particularly effective against swine flu. This infection can be combated by mixing one of the compounds into the infested animal's forage. For most purposes, the compounds are used in such an amount that one obtains from 0.0001 to 0.1% by weight of active compound calculated on the total amount by weight consumed, preferably from 0.001 to 0.02% by weight.
Et særlig viktig preparat for dette formål er et konsentrat som er egnet til salg til gårdbrukere og andre som driver feavl, for tilsetning til dyrenes for i passende mengder. Slike konsentrater inneholder i alminnelighet fra 0,5 til 95 vekt% av den aktive for bindelse sammen med et findelt fast stoff, fortrinnsvis mel, som f. eks. hvetemel, mais-, mel, soyabønnemel eller bomullsfrømel. I av-hengighet av det dyr som skal fores kan det faste stoff som anvendes være formalt korn, trekull, Fullerjord, østerskall eller lignende. Findelt attapulgit bg bentonit kan anvendes, og disse materialer virker også som faste dispergeringsmidler. A particularly important preparation for this purpose is a concentrate which is suitable for sale to farmers and others who breed cattle, for addition to the animals' feed in suitable quantities. Such concentrates generally contain from 0.5 to 95% by weight of the active for binding together with a finely divided solid substance, preferably flour, such as e.g. wheat flour, corn flour, soybean flour or cottonseed meal. Depending on the animal to be fed, the solid material used can be formal grain, charcoal, Fuller's earth, oyster shell or the like. Finely divided attapulgite bg bentonite can be used, and these materials also act as solid dispersants.
Forstoffene og de ovenfor beskrevne konsentrater kan dessuten inneholde andre be-standdeler som anvendes i forkonsentrater eller dyrefor. Blant andre særlig viktige til-setningsmidler er proteinstoffer, kullhydra-ter, fettstoffer, vitaminer, mineraler og anti-biotika. The precursors and the concentrates described above may also contain other ingredients that are used in precursor concentrates or animal feed. Among other particularly important additives are proteins, carbohydrates, fats, vitamins, minerals and antibiotics.
I det følgende beskrives som eksempler nogen utførelsesformer for oppfinnelsen. In the following, some embodiments of the invention are described as examples.
Eksempel 1. Example 1.
Ekvimolekylære mengder av 1-aminoadamantan og methyljodid oppvarmes i ca. 12 timer under tilbakeløpskjøling i ca. 1 liter l Equimolecular amounts of 1-aminoadamantane and methyl iodide are heated for approx. 12 hours under reflux cooling for approx. 1 liter l
xylen. Efter reaksjonstidens slutt avkjøles og filtreres reaksjonsblandingen. Det erholdte xylene. After the end of the reaction time, the reaction mixture is cooled and filtered. It obtained
faste produkt omrøres derefter i 500 ml vann solid product is then stirred in 500 ml of water
inneholdende en ekvimolekylær mengde na-triumoxyd. Det ønskede produkt oppsamles ved filtrering. containing an equimolecular amount of sodium oxide. The desired product is collected by filtration.
Under anvendelse av den ovenfor angitte fremgangsmåte kan der fremstilles andre forbindelser som tilsvarer den generelle formel (I) under anvendelse av de reaksjons-komponenter som er oppført nedenfor, hvorved man får de produkter som likeledes er oppført nedenfor i eksempler 2—14. I disse bringes altså ekvimolekylære deler av 1-aminoadamantan og de oppførte reaksjonskom-ponenter under de betingelser som er angitt i eksempel 1, hvorefter de erholdte produkter isoleres på den i eksempel 1 angitte måte. Using the above-mentioned method, other compounds corresponding to the general formula (I) can be prepared using the reaction components listed below, whereby the products which are also listed below in examples 2-14 are obtained. In these, equimolecular parts of 1-aminoadamantane and the listed reaction components are brought under the conditions indicated in example 1, after which the products obtained are isolated in the manner indicated in example 1.
Eksempel 15. Example 15.
Man leder vannfritt hydrogenklorid inn Anhydrous hydrogen chloride is introduced
i en oppløsning av 1-N^methylaminoadamantan i ether. Det herved dannede hydroklorid oppløses i varm acetonitril ved hjelp av en liten mengde methanol. Hydrokloridet ut-krystalliserer fra den avkjølte oppløsning i form av grå krystaller med smp. 226° C (tem-peratur gradientblokk). Utbyttet er 11,1 g (79 %). Til analyse omkrystalliseres der en porsjon én gang fra ethanol og én gang fra en blanding av acetonitril og methanol. Denne porsjon tørres derefter ved 100° C i 24 timer under anvendelse av en oljepumpe. Smp. 250 —251° C. in a solution of 1-N^methylaminoadamantane in ether. The hydrochloride thus formed is dissolved in hot acetonitrile with the aid of a small amount of methanol. The hydrochloride crystallizes out from the cooled solution in the form of gray crystals with m.p. 226° C (temperature gradient block). The yield is 11.1 g (79%). For analysis, a portion is recrystallized once from ethanol and once from a mixture of acetonitrile and methanol. This portion is then dried at 100° C for 24 hours using an oil pump. Temp. 250 -251° C.
Analyse: Analysis:
Beregnet for CnH20NCl: Calculated for CnH20NCl:
C = 65,48; H = 9,99; N = 6,94 C = 65.48; H = 9.99; N = 6.94
Funnet: Found:
C = 65,74; H = 10,36; N = 6,73 C = 65.74; H = 10.36; N = 6.73
C = 65,57; H = 9,98; N = 7,11 C = 65.57; H = 9.98; N = 7.11
Den fremstillede forbindelse viser meget god aktivitet ved standard-vevkulturforsøk med influensa A (WSN, svineinfluensa) og influensa A-2 (Jap 305, JPC, Michigan A/AA), og forbindelsen viser også utmerket in vivo-aktivitet i mus mot influensa A (svineinfluensa) og influensa A-2 (JPC, Michigan A/AA). The prepared compound shows very good activity in standard tissue culture tests with influenza A (WSN, swine flu) and influenza A-2 (Jap 305, JPC, Michigan A/AA), and the compound also shows excellent in vivo activity in mice against influenza A (swine flu) and influenza A-2 (JPC, Michigan A/AA).
De produkter som fremstilles ved den her omhandlede fremgangsmåte lar seg lett omdanne til tertiære aminer ved den i eksempel 1 beskrevne fremgangsmåte. Dette illu-streres i de følgende eksempler 16—20 som er sammenfattet i nedenstående tabell, i hvilken kolonnen med betegnelsen «produkt fra eksempel nr.» henviser til produktet fra det av de foran stående eksempler, som har dette nummer og som ny anvendes som reaktant. Alkyleringsmidlet er angitt i tredje kolonne, og i den siste kolonne er det resulterende produkt oppført. The products produced by the method described here can easily be converted into tertiary amines by the method described in example 1. This is illustrated in the following examples 16-20, which are summarized in the table below, in which the column labeled "product from example no." refers to the product from the preceding examples, which has this number and is used as a reactant when new. The alkylating agent is listed in the third column, and in the last column the resulting product is listed.
Eksempel 21. Example 21.
I en 100 ml kolbe med magnetisk røre-verk og tilbakeløpskjøler føres der inn 7,55 g (0,050 mol) 1-aminoadamantan, 6,13 g (0,050 mol) ethylkloracetat, 5,00 g (0,060 mol) na-triumbikarbonat og 20 ml methanol. Blan-dingen oppvarmes under tilbakeløpskjøling natten over. Uoppløst materiale frafiltreres, filtratet inndampes til tørrhet, residuet opp-løses i 60 ml 1 N saltsyre, og oppløsningen tilsettes 10 ml 70 %'s perklorsyre. Det herved utfelte perklorat av 1-N-adamantylgly-cinethylester frafiltreres, vaskes med koldt vann og tørres, hvorved man får 8,3 g (49 %) hvite krystaller, som ved oppvarmning spaltes over et bredt temperaturområde omkring ca. 155° C. 7.55 g (0.050 mol) 1-aminoadamantane, 6.13 g (0.050 mol) ethyl chloroacetate, 5.00 g (0.060 mol) sodium bicarbonate and 20 ml of methanol. The mixture is heated under reflux overnight. Undissolved material is filtered off, the filtrate is evaporated to dryness, the residue is dissolved in 60 ml of 1 N hydrochloric acid, and 10 ml of 70% perchloric acid is added to the solution. The thus precipitated perchlorate of 1-N-adamantylglycine ethyl ester is filtered off, washed with cold water and dried, whereby 8.3 g (49%) of white crystals are obtained, which, when heated, split over a wide temperature range of approx. 155°C.
Den frie base regenereres med 10 %'s na-triumhydroxydoppløsning. Efter ekstraksjon med ether og inndampning destilleres det herved erholdte oljeaktige produkt, hvorved man får 1,58 g (9 %) 1-N-adamantylgylcyinethyl-ester som en væske med kp. 85—89° C ved 0,24 mm Hg og n \f = 1,5032. Analyse: The free base is regenerated with 10% sodium hydroxide solution. After extraction with ether and evaporation, the oily product thus obtained is distilled, whereby 1.58 g (9%) of 1-N-adamantyl gylcyine ethyl ester is obtained as a liquid with bp. 85-89° C at 0.24 mm Hg and n \f = 1.5032. Analysis:
Beregnet for C^H^NC^: Calculated for C^H^NC^:
C = 70,85; H = 9,77; N = 5,91 C = 70.85; H = 9.77; N = 5.91
Funnet: Found:
C = 70,04; H = 9,36; N = 6,44 C = 70.04; H = 9.36; N = 6.44
Produktet viser aktivitet mot Michigan A/AA-, svine- og vacciniavira. The product shows activity against Michigan A/AA, swine and vaccinia viruses.
Eksempel 22. Example 22.
I en 145 ml autoklav av rustfritt stål føres der inn 15,1 g (0,1 mol) 1-aminoadamantan og 5 g (0,1 mol) ethylenoxyd. Den erholdte blanding oppvarmes til 70° C i 12 timer, hvorpå den inndampes til tørrhet. Residuet omkrystalliseres fra toluen, hvorved man får 5,29 g produkt med smp. 75—84° C. Dette produkt destilleres, hvorved man får 2 fraksjoner, nemlig Fraksjon I: 1-(2-hydroxyethylamino)-adamantan k.p. 122—124° C/0,05 mm, sm.p. 97—99° C, vekt 0,99 g. 15.1 g (0.1 mol) of 1-aminoadamantane and 5 g (0.1 mol) of ethylene oxide are introduced into a 145 ml stainless steel autoclave. The resulting mixture is heated to 70° C. for 12 hours, after which it is evaporated to dryness. The residue is recrystallized from toluene, whereby 5.29 g of product with m.p. 75—84° C. This product is distilled, whereby 2 fractions are obtained, namely Fraction I: 1-(2-hydroxyethylamino)-adamantane b.p. 122—124° C/0.05 mm, m.p. 97-99° C, weight 0.99 g.
Fraksjon II: Faction II:
1- (bis-2-hydroxyethylamino) -adamantan k.p. 158° C/0,05 mm, sm.p. 113—114° C, vekt 1,62 g. 1-(bis-2-hydroxyethylamino)-adamantane b.p. 158° C/0.05 mm, m.p. 113-114° C, weight 1.62 g.
Analyse: Analysis:
Beregnet for Ci2H21NO (fraksjon I): C 73,80 %; H 10,85 % ; N 7,17 % Calculated for Ci2H21NO (fraction I): C 73.80%; H 10.85%; N 7.17%
Funnet: Found:
C 73,19 %; H 10,73 %; N 6,89 % Analyse: Beregnet for C14H25N02 (fraksjon II) : C 70,25 %; H 10,53 % N 5,85 % C 73.19%; H 10.73%; N 6.89% Analysis: Calculated for C14H25N02 (fraction II) : C 70.25%; H 10.53% N 5.85%
Funnet: Found:
N 5,81 %. N 5.81%.
Begge disse fraksjoner viser ved forsøk på mus aktivitet mot svineinfluensa og Michigan A/AA-influensa. Forbindelser som omfattes av den foran angitte generelle formel I, eller nærliggende forbindelser kan også fremstilles således som beskrevet i patentinnehaverens patenter nr. 113 375, 113 377, 113 378 og 113 379. Both of these fractions show activity against swine flu and Michigan A/AA flu when tested on mice. Compounds covered by the general formula I stated above, or similar compounds can also be prepared as described in the patent holder's patents no. 113 375, 113 377, 113 378 and 113 379.
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NO853600L NO853600L (en) | 1987-03-16 |
NO159586B true NO159586B (en) | 1988-10-10 |
NO159586C NO159586C (en) | 1989-01-18 |
Family
ID=19888473
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO853600A NO159586C (en) | 1985-09-13 | 1985-09-13 | PROCEDURE FOR ANAEROBIC WASTE CLEANING. |
Country Status (1)
Country | Link |
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NO (1) | NO159586C (en) |
-
1985
- 1985-09-13 NO NO853600A patent/NO159586C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO159586C (en) | 1989-01-18 |
NO853600L (en) | 1987-03-16 |
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