NO140378B - PROCEDURE FOR PREPARING 1- (3,5-DIHYDROXYPHENYL) -1-HYDROXY-2- (1-METHYL-2- (4-HYDROXYPHENYL) -ETHYL) -AMINOETANE - Google Patents

PROCEDURE FOR PREPARING 1- (3,5-DIHYDROXYPHENYL) -1-HYDROXY-2- (1-METHYL-2- (4-HYDROXYPHENYL) -ETHYL) -AMINOETANE Download PDF

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Publication number
NO140378B
NO140378B NO750922A NO750922A NO140378B NO 140378 B NO140378 B NO 140378B NO 750922 A NO750922 A NO 750922A NO 750922 A NO750922 A NO 750922A NO 140378 B NO140378 B NO 140378B
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compound
hydroxyphenyl
ethyl
hydroxy
methyl
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NO750922A
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Norwegian (no)
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NO750922L (en
NO140378C (en
Inventor
Anton Mentrup
Kurt Schromm
Ernst-Otto Renth
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Boehringer Sohn Ingelheim
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Publication of NO140378C publication Critical patent/NO140378C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Description

Denne oppfinnelse angår en ny fremgangsmåte for frem- This invention relates to a new method for producing

stilling av 1-(3,5-dihydroksyfenyl)-l-hydroksy-2-[l-metyl-2-(4-hydroksyfenyl)etyl]-aminoetan med formelen position of 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-[1-methyl-2-(4-hydroxyphenyl)ethyl]-aminoethane with the formula

eventuelt i form av diastereomerene og de tilsvarende syre- possibly in the form of the diastereomers and the corresponding acid-

addisjonssalter. addition salts.

Den nye fremgangsmåte karakteriseres ved at man på i og The new method is characterized by the fact that in and

for seg kjent måte substituerer 3,5-dihydroksyacetofenon til 3,5-arylmetoksyforbindelsen, 3,5-arylmetoksyacetofenon oksyderes til det tilsvarende glyoksalderivat, dette, eventuelt efter over- in a manner known per se, 3,5-dihydroxyacetophenone substitutes for the 3,5-arylmethoxy compound, 3,5-arylmethoxyacetophenone is oxidized to the corresponding glyoxal derivative, this, possibly after over-

føring til halvacetalet ved innvirkning av en lavere alkohol, leading to the hemiacetal by the action of a lower alcohol,

omsettes med 1-(4-hydroksyfenyl)-propyl-2-amin resp. et l-(4-arylmetoksyfenyl)-propyl-2-amin til forbindelsen med formelen: is reacted with 1-(4-hydroxyphenyl)-propyl-2-amine resp. a 1-(4-arylmethoxyphenyl)-propyl-2-amine to the compound of the formula:

hvor betyr en arylmetylrest og R_ hydrogen eller en arylmetyl- where an arylmethyl residue and R_ means hydrogen or an arylmethyl-

rest, forbindelsen 2 reduseres med natriumborhydrid i et egnet oppløsningsmiddel til forbindelsen residue, the compound 2 is reduced with sodium borohydride in a suitable solvent for the compound

derefter foretas eventuelt en diastereomerseparering før eller efter avspaltning av beskyttelsesgruppene, og eventuelt fremstilles ved vanlige metoder de tilsvarende syreaddisjonssalter resp. frie baser. then, if necessary, diastereomer separation is carried out before or after cleavage of the protective groups, and if necessary, the corresponding acid addition salts or free bases.

Arten av restene og R2 er av underordnet betydning for reaksjonsforløpet. Det er imidlertid hensiktsmessig å benytte de enklest mulige rester R1 og R2 i utgangsstoffene. Derfor anvendes fortrinnsvis slike utgangsstoffer hvor betyr benzyl og R2 betyr hydrogen eller benzyl. The nature of the residues and R2 is of minor importance for the course of the reaction. However, it is appropriate to use the simplest possible residues R1 and R2 in the starting materials. Therefore, such starting materials are preferably used where means benzyl and R 2 means hydrogen or benzyl.

Reduksjonen av forbindelsen med ovenstående formel 2 ut-føres i et for reduksjoner med natriumborhydrid egnet oppløsnings-middel, f.eks. en lavere alkohol (metanol, etanol, propanol), dioksan, tetrahydrofuran, eventuelt blandet med hverandre eller med vann, ved temperaturer mellom ca. 0°C og romtemperatur, eventuelt også ved lavere eller høyere temperaturer. The reduction of the compound with the above formula 2 is carried out in a solvent suitable for reductions with sodium borohydride, e.g. a lower alcohol (methanol, ethanol, propanol), dioxane, tetrahydrofuran, optionally mixed with each other or with water, at temperatures between approx. 0°C and room temperature, possibly also at lower or higher temperatures.

Den hydrogenolytiske avspaltning av beskyttelsesgruppene fra forbindelsen med ovenstående formel 3 utføres ved i og for seg kjente metoder. Som katalysator anvendes f.eks. hensiktsmessig platina, palladium, Raney-nikkel og rhodium og som oppløsnings-middel særlig metanol. Temperatur og trykk kan velges innenfor The hydrogenolytic removal of the protective groups from the compound with the above formula 3 is carried out by methods known per se. As a catalyst, e.g. suitable platinum, palladium, Raney nickel and rhodium and, as a solvent, methanol in particular. Temperature and pressure can be selected within

et bredt område, men fortrinnsvis arbeider man ved romtemperatur eller svakt forhøyet temperatur og ved trykk mellom normaltrykk og a wide range, but preferably one works at room temperature or slightly elevated temperature and at pressure between normal pressure and

IO atm. IO atm.

De diastereomere antipodepar oppnås ved at man enten skiller produktet fra reduksjonen (forbindelse 3) på grunnlag av den ulike oppløselighet av de diastereomere antipodepar, og derefter avspalter beskyttelsesgruppene, eller ved at man spalter den blanding av diastereomerene 1 som oppnås efter avspaltning av beskyttelses gruppene fra 3. The diastereomeric antipode pairs are obtained by either separating the product from the reduction (compound 3) on the basis of the different solubility of the diastereomeric antipode pairs, and then cleaving off the protecting groups, or by cleaving the mixture of the diastereomers 1 obtained after removal of the protective groups from 3.

Syreaddisjonssaltene fremstilles fra de erholdte forbindelser på vanlig måte. Hvis man ønsker de frie baser, kan de eventuelt frigjøres fra de først erholdte syreaddisjonssalter på vanlig måte. The acid addition salts are prepared from the compounds obtained in the usual way. If the free bases are desired, they can possibly be released from the first obtained acid addition salts in the usual way.

I det følgende er gjengitt en sammenligning mellom den kjente fremgangsmåte og foreliggende fremgangsmåte for fremstilling av forbindelser med formel 1. In the following, a comparison is given between the known method and the present method for producing compounds of formula 1.

(Fenoterol er det generiske navn for handelsproduk-tet som kan fremstilles ifølge oppfinnelsen). (Fenoterol is the generic name for the commercial product that can be produced according to the invention).

Beregnet på grunnlag av utgangsmaterialet 3,5-dihydroksyacetofenon utgjør det samlede utbytte 6,8% av det teoretiske. Calculated on the basis of the starting material 3,5-dihydroxyacetophenone, the total yield is 6.8% of the theoretical.

Det samlede utbytte ved fremgangsmåten er således 22,1^. The total yield of the method is thus 22.1^.

Foreliggende fremgangsmåte gir således med færre trinn (trinnene 3 og 4 foretas dessuten i samme reaktor) og med vesentlig høyere totalt utbytte, det ønskede sluttprodukt. Sluttproduktet som oppnås ved hjelp av foreliggende fremgangsmåte, utmerker seg dessuten ved en høyere renhet. The present method thus provides the desired end product with fewer steps (steps 3 and 4 are also carried out in the same reactor) and with a significantly higher total yield. The end product obtained by means of the present method is also distinguished by a higher purity.

Den nye fremgangsmåte utmerker seg således fremfor de kjente fremgangsmåter for fremstilling av forbindelsene med formel 1 ved at den er enkel å utføre og overraskende fører til et meget rent sluttprodukt med høyt utbytte uten spesiell rensning. The new method thus excels over the known methods for producing the compounds of formula 1 in that it is simple to carry out and surprisingly leads to a very pure end product with a high yield without special purification.

Den nye fremgangsmåte skal illustreres nærmere ved hjelp av eksemplet: The new procedure will be illustrated in more detail using the example:

Eksempel Example

a) 3, 5- dibenzyloksyfenylglyoksal- etylacetal 332 g (1 mol) 3,5-dibenzyloksyaeetofenon kokes med 105,2 g a) 3,5-dibenzyloxyphenylglyoxal-ethyl acetal 332 g (1 mol) 3,5-dibenzyloxyaetophenone is boiled with 105.2 g

(0,95 mol) selendioksyd i en blanding av 1200 ml dioksan og 50 ml vann under tilbakeløpskjøling, inntil ca. 72 g selen (0.95 mol) selenium dioxide in a mixture of 1200 ml of dioxane and 50 ml of water under reflux, until approx. 72 g selenium

er utfelt. Dioksan-oppløsningen som er renset over aktivt kull, inndampes,og residuet oppløses i varm tilstand i 1 liter 90 prosentig etanol. Oppløsningen kimpodes. Den resulterende krystallisasjon er fullstendig etter 4 timer under avkjøling. Det avsugde produkt omkrystalliseres fra den 10-dobbelte mengde etanol, og man får 317 g (80,9$ av de teoretiske) 3,5-dibenzyloksyfenylglyoksal-etylacetal. is precipitated. The dioxane solution that has been purified over activated charcoal is evaporated, and the residue is dissolved in a warm state in 1 liter of 90 per cent ethanol. The solution is seeded. The resulting crystallization is complete after 4 hours under cooling. The aspirated product is recrystallized from the 10-fold amount of ethanol, and 317 g (80.9% of the theoretical) of 3,5-dibenzyloxyphenylglyoxal-ethyl acetal are obtained.

b) 1-( 3, 5- dibenzyloksyfenyl)- l- hydroksy- 2[ l- metyl- 2-( 4- hydroksy-feny1)- ety1]- aminoetan b) 1-(3,5-dibenzyloxyphenyl)-1-hydroxy-2[1-methyl-2-(4-hydroxy-phenyl)-ethyl]-aminoethane

107,8 g (0,275 mol) 3,5-dibenzyloksyfenylglyoksal-etylacetal og 37,75 g (0,25 mol) l-(4-hydroksyfenyl)-propyl-2-amin oppløses i. 1 liter etanol ved 50°C, får stå i 3 timer ved romtemperatur og filtreres deretter over aktivt kull. I oppløsningen, som er avkjølt til o°C, innføres 18 g natriumborhydrid i små por-sjoner. Etter henstand natten over surgjøres under god av-kjøling med 250 ml 4 n saltsyre, og alkoholen avdestilleres i vakuum. 107.8 g (0.275 mol) of 3,5-dibenzyloxyphenylglyoxal-ethyl acetal and 37.75 g (0.25 mol) of 1-(4-hydroxyphenyl)-propyl-2-amine are dissolved in 1 liter of ethanol at 50°C, allowed to stand for 3 hours at room temperature and then filtered over activated carbon. Into the solution, which has been cooled to o°C, 18 g of sodium borohydride are introduced in small portions. After standing overnight, acidify under good cooling with 250 ml of 4 N hydrochloric acid, and the alcohol is distilled off in a vacuum.

Ved tilsetning av vann og ammoniakk frigjøres basen som opptas med etylacetat. Etter avdestillering av etylacetatet When water and ammonia are added, the base is released, which is taken up with ethyl acetate. After distilling off the ethyl acetate

er det tilbake i residuet 148 g av tittelforbindelsen III. 148 g of the title compound III remain in the residue.

c) Spaltning av forbindelsen III i diastereomerene Illa og Illb 148 g av forbindelsen III i 1,5 1 etylacetat tilsettes 36 g c) Cleavage of the compound III into the diastereomers Illa and Illb 148 g of the compound III in 1.5 1 ethyl acetate is added to 36 g

maleinsyre som er oppløst i 300 ml etylacetat. Maleinatet av diastereomeren Illa utkrystalliserer i et utbytte på 55 g. Maleinatet av Illa oppviser et smeltepunkt på 136°C (fra acetonitril). Moderluten behandles med 2 n ammoniakkoppløsning og deretter med vann. Den fraskilte etylacetatfase tørres og avdestilleres godt. Residuet som er opptatt i 500 ml etylacetat, gir etter surgjøring med eterisk saltsyre til pH 4,2 hydrokloridet av diastereomeren IEIb. Etter omkrystal-lisering fra den femtendobbelte mengde av acetonitril erholdes 47,5 g av isomeren Illb som hydroklorid med smeltepunkt 176°C. maleic acid which is dissolved in 300 ml of ethyl acetate. The maleate of the diastereomer Illa crystallizes out in a yield of 55 g. The maleate of Illa has a melting point of 136°C (from acetonitrile). The mother liquor is treated with 2 n ammonia solution and then with water. The separated ethyl acetate phase is dried and distilled off well. The residue, which is taken up in 500 ml of ethyl acetate, gives, after acidification with ethereal hydrochloric acid to pH 4.2, the hydrochloride of the diastereomer IEIb. After recrystallization from the fifteenfold amount of acetonitrile, 47.5 g of the isomer IIIb is obtained as hydrochloride with a melting point of 176°C.

Ved opparbeidelse av moderluten kan utbyttet av diastereomerene Illa og Illb forbedres ytterligere. When working up the mother liquor, the yield of the diastereomers Illa and Illb can be further improved.

d) 1-( 3, 5- dihydroksyfenyl)- l- hydroksy- 2-[ l- metyl- 2-( 4- hydroksyfenyl)-etyl]- aminoetan- hydrobromid som rene diastereomerer d) 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-[1-methyl-2-(4-hydroxyphenyl)-ethyl]- aminoethane hydrobromide as pure diastereomers

9 g III-a-maleinat oppløses i vann og tilsettes 15 ml konsentrert Dissolve 9 g of III-a-maleinate in water and add 15 ml concentrated

ammoniakk. Etter 2 gangers utdryssing med etylacetat tørres oppløsningen og destilleres. Residuet overføres til hydrobromidet III i acetonitril med 49 prosentig bromhydrogensyre. Utbyttet utgjør 8,35 g (98,555), smeltepunktet er 155°C. Hydrobromidet oppløses i 120 ml metanol og hydrogeneres med Pd/C ved romtemperatur under normaltrykk inntil den teoretiske hydrogen-mengde er opptatt. Man får derved 5,3 g av forbindelsen Ia som hydrobromid med smeltepunkt 230°C. ammonia. After spraying twice with ethyl acetate, the solution is dried and distilled. The residue is transferred to the hydrobromide III in acetonitrile with 49 percent hydrobromic acid. The yield is 8.35 g (98.555), the melting point is 155°C. The hydrobromide is dissolved in 120 ml of methanol and hydrogenated with Pd/C at room temperature under normal pressure until the theoretical amount of hydrogen is taken up. This gives 5.3 g of the compound Ia as hydrobromide with a melting point of 230°C.

Ved hydrogenering av det isomere Elb-hydroklorid oppnås på On hydrogenation of the isomeric E1b hydrochloride is obtained

analog måte isomeren Ib som hydroklorid i et utbytte på 96%, analogous way the isomer Ib as hydrochloride in a yield of 96%,

smeltepunkt 155-l88°C. melting point 155-188°C.

e) l-( 3- 5- dihyroksyfenyl)- l- hydroksy- 2-[ l- metyl- 2-( 4- hydroksyfenyl) - etyl]- aminoetan- hydrobromid som diastereomerblanding e) l-(3-5-dihydroxyphenyl)-l-hydroxy-2-[l-methyl-2-(4-hydroxyphenyl)-ethyl]- aminoethane hydrobromide as diastereomer mixture

14,8 g av forbindelsen III oppløses i 150 ml metanol og omdannes til hydrobromidet ved tilsetning av bromhydrogensyre. Hydrogenering foretas etter tilsetning av Pd/C inntil den teoretiske mengde hydrogen er opptatt. Diastereomerblandingen Ia og Ib isoleres etter avdestillering av metanolen ved tilsetning av 25 ml vann og 25 ml konsentrert bromhydrogensyre til residuet 14.8 g of compound III are dissolved in 150 ml of methanol and converted to the hydrobromide by addition of hydrobromic acid. Hydrogenation is carried out after adding Pd/C until the theoretical amount of hydrogen is taken up. The diastereomer mixture Ia and Ib is isolated after distilling off the methanol by adding 25 ml of water and 25 ml of concentrated hydrobromic acid to the residue

i et utbytte på 95%, smeltepunkt 191-199°C in a yield of 95%, melting point 191-199°C

f) Fraskillelse av diastereomeren Ia fra diastereomerblandingen f) Separation of the diastereomer Ia from the diastereomer mixture

For isolering av diastereomeren Ia og Ib kokes 18 g av den For the isolation of the diastereomer Ia and Ib, 18 g of it are boiled

i henhold til e) erholdte blanding med 55 ml isopropanol, og residuet omfelles fra metanol/kloroform. Man får 6,5 g av diastereomeren Ia, smeltepunkt 227-230°C. according to e) mixture obtained with 55 ml of isopropanol, and the residue is precipitated from methanol/chloroform. 6.5 g of the diastereomer Ia is obtained, melting point 227-230°C.

Claims (1)

Fremgangsmåte for fremstilling av 1-(3,5-dihydroksyfenyl)-l-hydroksy-2-[l-metyl-2-(4-hydroksyfenyl)-etyl]-aminoetan, eventuelt i form av diastereomerene og de tilsvarende syre-addis jonssalter , karakterisert ved at man på i og for seg kjent måte substituerer 3,5-dihydroksyacetofenon til 3,5-arylmetoksyforbindelsen, 3,5-arylmetoksyacetofenon oksyderes til det tilsvarende glyoksalderivat, dette, eventuelt efter overføring til halvacetalet ved innvirkning av en lavere alkohol, omsettes med 1-(4-hydroksyfenyl)-propyl-2-amin resp.Process for the production of 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-[1-methyl-2-(4-hydroxyphenyl)-ethyl]-aminoethane, optionally in the form of the diastereomers and the corresponding acid addition salts , characterized in that 3,5-dihydroxyacetophenone is substituted for the 3,5-arylmethoxy compound in a manner known per se, 3,5-arylmethoxyacetophenone is oxidized to the corresponding glyoxal derivative, this, optionally after transfer to the hemiacetal by the action of a lower alcohol, is reacted with 1-(4-hydroxyphenyl)-propyl-2-amine resp. et 1-(4-arylmetoksyfenyl)-propyl-2-amin til forbindelsen med formelen:a 1-(4-arylmethoxyphenyl)-propyl-2-amine to the compound of the formula: hvor betyr en arylmetylrest og R2 hydrogen eller en arylmetylrest, forbindelsen 2 reduseres med natriumborhydrid i et egnet oppløsningsmiddel til forbindelsenwhere an arylmethyl radical and R2 means hydrogen or an arylmethyl radical, the compound 2 is reduced with sodium borohydride in a suitable solvent for the compound derefter foretas eventuelt en diastereomerseparering før eller efter avspaltning av beskyttelsesgruppene, og eventuelt fremstilles ved vanlige metoder de tilsvarende syreaddisjonssalter resp. frie baser.then, if necessary, diastereomer separation is carried out before or after cleavage of the protective groups, and if necessary, the corresponding acid addition salts or free bases.
NO750922A 1974-03-19 1975-03-18 PROCEDURE FOR PREPARING 1- (3,5-DIHYDROXYPHENYL) -1-HYDROXY-2- (1-METHYL-2- (4-HYDROXYPHENYL) -ETHYL) -AMINOETANE NO140378C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE2413102A DE2413102C3 (en) 1974-03-19 1974-03-19 Process for the production of l- (3,5-dihydroxyphenyl) -t-hydroxy-2-square brackets on 1-methyl-2- (4-hydroxyphenyl) -ethyl] -aminoethane

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Publication Number Publication Date
NO750922L NO750922L (en) 1975-09-22
NO140378B true NO140378B (en) 1979-05-14
NO140378C NO140378C (en) 1979-08-22

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JP (1) JPS50131936A (en)
AT (1) AT339884B (en)
BG (1) BG27075A3 (en)
CH (1) CH607993A5 (en)
CS (1) CS181290B2 (en)
DE (1) DE2413102C3 (en)
DK (1) DK136184C (en)
ES (1) ES435498A1 (en)
FI (1) FI62528C (en)
HU (1) HU169834B (en)
NO (1) NO140378C (en)
SE (1) SE423091B (en)
YU (1) YU37111B (en)

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JPS5256217A (en) * 1975-11-01 1977-05-09 Nissan Motor Co Ltd Exhaust purifying system for internal combustion engine
CA1145766A (en) * 1978-07-03 1983-05-03 Jack Mills Optically active phenethanolamines and method for increasing cardiac contractility
CH653322A5 (en) * 1982-12-01 1985-12-31 Siegfried Ag METHOD FOR PRODUCING PHENYLETHANOLAMINES.
WO2014108449A1 (en) 2013-01-08 2014-07-17 Atrogi Ab A screening method, a kit, a method of treatment and a compound for use in a method of treatment
GB201714745D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714734D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714740D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714736D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB202205895D0 (en) 2022-04-22 2022-06-08 Atrogi Ab New medical uses

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ES435498A1 (en) 1976-12-01
DK136184C (en) 1978-03-20
FI750725A (en) 1975-09-20
ATA153975A (en) 1977-03-15
SE7503083L (en) 1975-09-22
BG27075A3 (en) 1979-08-15
AT339884B (en) 1977-11-10
DE2413102C3 (en) 1980-09-11
NO750922L (en) 1975-09-22
YU67375A (en) 1983-04-27
JPS50131936A (en) 1975-10-18
SE423091B (en) 1982-04-13
NO140378C (en) 1979-08-22
DK110175A (en) 1975-09-20
DE2413102A1 (en) 1975-10-09
CH607993A5 (en) 1978-12-15
DK136184B (en) 1977-08-29
YU37111B (en) 1984-08-31
HU169834B (en) 1977-02-28
DE2413102B2 (en) 1980-01-17
CS181290B2 (en) 1978-03-31
FI62528C (en) 1983-01-10
FI62528B (en) 1982-09-30

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