DK142843B - Analogous process for preparing 2-amino-2 ', 6'-propionoxylidide or acid addition salts thereof. - Google Patents

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01) FREMLÆ66ELSESSKRIFT 142843 'OX01) PUBLICATION MANUAL 142843 'OX

DANMARK (si) int.ci.3 c 07 c 103/50 §(21) Ansøgning nr. 3052/72 (22) Indleveret den 24. Jul. 1 gyg (24) Løbedag 24. Jul. 1972 (44) Ansøgningen fremlagt og fremleggeleeeskriftet offentliggjort den 9· f eb. 1 981DENMARK (si) int.ci.3 c 07 c 103/50 Section (21) Application No. 3052/72 (22) Filed on 24 Jul. 1 gyg (24) Race day 24 Jul. 1972 (44) The application presented and the presentation document published on 9 · fb. 1 981

DIREKTORATET FORDIRECTORATE OF

PATENT-OG VAREMÆRKEVÆSENET <30> Prioritet begeret fra denPATENT AND TRADE MARKET <30> Priority cup from it

28. Jul. 1971, 167031, US28 Jul. 1971, 167031, US

<71> AKTIEBO LAGET HAESSLE, Kaerragatan 5, 431 83 Moelndal, SE.<71> AKTIEBO LAGET HAESSLE, Kaerragatan 5, 431 83 Moelndal, SE.

(72) Opfinder: Robert Nlchol Boyes, 16 Homestead Avenue, Auburn, Worcester,(72) Inventor: Robert Nlchol Boyes, 16 Homestead Avenue, Auburn, Worcester,

Mass., US: Benjamin Randall Duce, 10 Belknap Street, Wes thorough, Wor= cester, Mass., US: Emil Richard Smith, 5 Bryant Avenue, Shrewsbury, Worcester, Mass., US: Eugene WllTlam Byrnes, 191 Nola Drive Holden, Worcester, Mass., US.Mass., US: Benjamin Randall Duce, 10 Belknap Street, West thoroughfare, Wor = cester, Mass., US: Emil Richard Smith, 5 Bryant Avenue, Shrewsbury, Worcester, Mass., US: Eugene WllTlam Byrnes, 191 Nola Drive Holden , Worcester, Mass., US.

(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:

Kontor for Industriel Eneret v. Svend Scheming.Office of Industrial Eneret v. Svend Scheming.

(54) Analogifremgangsmåde til fremstilling af 2-amino-2l,6* -propiono-xyli* did eller syreadditionsealte heraf.(54) Analogous process for the preparation of 2-amino-2,1,6 * -propiono-xylidene or acid addition salts thereof.

Den foreliggende opfindelse angår en analogifremgangsmå-de til fremstilling af den hidtil ukendte forbindelse 2-amino-2',6'-propiono-xylidid eller syreadditionssalte heraf, hvilken forbindelse er anvendelig som et antiarrytmisk lægemiddel til 5 pattedyr.The present invention relates to an analogous process for the preparation of the novel compound 2-amino-2 ', 6'-propionoxylidide or acid addition salts thereof, which compound is useful as an antiarrhythmic drug for mammals.

Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del omhandlede.The method according to the invention is characterized by the characterizing part of the claim.

Lige siden indføringen af intensiv koronarpleje har man lagt vægt på behandlingen af ventrikulære ekstrasystoler og 10 andre hjertearrytmier. Ingen konventionelle lægemidler er fuldstændigt tilfredsstillende ved langtidskontrol af sådanne arrytmier. Sådanne lægemidler som kinidin, prokainamid, pro- 2 142843 pranolol og difenylhydrantoin (phenytoin (Brit.Pharm.)) har været anvendt, men udviser uønskede bivirkninger. Visse fen-oxyderivater af aminopropan har også været undersøgt, men deres virkning på centralnervesystemet er en lignende som 5 phenytoins. (Proceedings of the British Pharmacological Society, Vol. 39, pp 183P, 1970). Foruden de ovennævnte forbindelser udviser også andre farmaceutiske præparater antiarryt-miske egenskaber. Fx er lokalbedøvelsesmidlet "Xylocain"® (lidokain), hvis kemiske navn er 2-diætylamino-2',6'-aceto-10 xylidid, et antiarrytmisk lægemiddel, der er egnet til intravenøs eller intramuskulær anvendelse (P.I. Parkinson m.fl.,Ever since the introduction of intensive coronary care, attention has been given to the treatment of ventricular extrasystoles and 10 other cardiac arrhythmias. No conventional drugs are completely satisfactory in long-term control of such arrhythmias. Such drugs as quinidine, procainamide, propanolol and diphenylhydantoin (phenytoin (Brit.Pharm.)) Have been used but exhibit undesirable side effects. Certain phenoxy-derivatives of aminopropane have also been studied, but their effect on the central nervous system is similar to that of 5 phenytoins. (Proceedings of the British Pharmacological Society, Vol. 39, pp. 183P, 1970). In addition to the above compounds, other pharmaceutical compositions also exhibit antiarrhythmic properties. For example, the local anesthetic "Xylocaine" (lidocaine), whose chemical name is 2-diethylamino-2 ', 6'-aceto-10 xylidide, is an antiarrhythmic drug suitable for intravenous or intramuscular use (P.I. Parkinson et al.,

Brit.Med.J., Vol. 2, pp. 29-30, 1970, og The Merck Index, 8th Ed., Merck & Company Inc., Rahway, New Jersey, 1968, p.Brit.Med.J., Vol. 2, pp. 29-30, 1970, and The Merck Index, 8th Ed., Merck & Company Inc., Rahway, New Jersey, 1968, p.

168), men det er ikke effektivt ved oral indgivelse på grund 15 af lav koncentration af lægemidlet i blodet (Eisinger og Hellier, Lancet, 1969, II, 1303 og Boyes m.fl., Clin. Pharmacol. Therap., 12, nr. 1, pp. 105-116, 1971). Når lidokain indgives oralt er der et betydeligt tab af lægemidlet, sandsynligvis på grund af funktionerne i leveren, gennem hvilken det meste 20 af lægemidlet skal passere umiddelbart efter adsorptionen fra tarmsystemet. Varigheden af de lidokainkoncentrationer, der kan opnås i blodet er også temmelig kort, hvorved en langvarig beskyttelse er udelukket.168), but it is not effective in oral administration due to low concentration of the drug in the blood (Eisinger and Hellier, Lancet, 1969, II, 1303 and Boyes et al., Clin. Pharmacol. Therap., 12, no. 1, pp. 105-116, 1971). When lidocaine is administered orally, there is a significant loss of the drug, probably due to the functions of the liver through which most 20 of the drug must pass immediately after adsorption from the intestinal system. The duration of the lidocaine concentrations obtainable in the blood is also quite short, thus excluding long-term protection.

Det er også kendt at visse 2-aminotetraliner udviser 25 antiarrytmiske egenskaber (D.M. Graeff m.fl., Journal of Medicinal Chemistry, Vol.14, pp. 60-62, 1971).It is also known that certain 2-aminotetralins exhibit 25 antiarrhythmic properties (D.M. Graeff et al., Journal of Medicinal Chemistry, Vol.14, pp. 60-62, 1971).

Fra Archiv der Pharmazie, bind 301 (1968), pp. 780-785, kendes en forbindelse med antiarrytmiske egenskaber, nemlig forbindelsen N-(N-dimetylalanyl)-2,6-dimetylanilin med formlen CH3 -V 9 ^ch, V\_NH-C-CH-N ^ =\ CH, XcH3 CH3 3From Archiv der Pharmazie, Vol. 301 (1968), pp. 780-785, a compound having antiarrhythmic properties is known, namely the compound N- (N-dimethylalanyl) -2,6-dimethylaniline of the formula CH 3 -V 9 _NH-C-CH-N ^ = \ CH, XcH3 CH3 3

Denne forbindelse er strukturelt set den nærmest beslægtede af de kendte forbindelser, hvilket lettest kan illu- 3 142843 streres ved at forbindelsen med den her benyttede terminologi kan betegnes 2-dimetylamino-2',6'-propiono-xylidid, dvs. denne kendte forbindelse adskiller sig kun fra den her omhandlede forbindelse ved de to metylgrupper på 2-aminogruppen.This compound is structurally the most closely related of the known compounds, which can be most easily illustrated by the compound having the terminology used herein being referred to as 2-dimethylamino-2 ', 6'-propionoxylidide, i.e. this known compound differs only from the present compound at the two methyl groups on the 2-amino group.

5 Den ved fremgangsmåden ifølge den foreliggende opfin delse fremstillede forbindelse 2-amino-2',6'-propiono-xylidid kan anvendes som antiarrytmisk lægemiddel. Den omhandlede forbindelse og dens terapeutisk acceptable salte giver selv ved oral indgift en forholdsvis høj koncentration af lægemidlet 10 i blodet. Varigheden af denne blodkoncentration er også forholdsvis lang.The compound 2-amino-2 ', 6'-propionoxylidide prepared by the process of the present invention can be used as an antiarrhythmic drug. The subject compound and its therapeutically acceptable salts provide a relatively high concentration of the drug 10 in the blood even with oral administration. The duration of this blood concentration is also relatively long.

Forbindelsen 2-amino-2',6'-propiono-xylidid har den viste strukturelle formel CH3 15 -NHCOCHNH2 ^ CH3The compound 2-amino-2 ', 6'-propionoxylidide has the structural formula shown CH3 15 -NHCOCHNH2 ^ CH3

Fremgangsmåden ifølge den foreliggende opfindelse til syntetisering af den nævnte forbindelse I kan hensigtsmæssigt gennemføres ved at en suspension af 2-brom-26'-propiono-xylidid i en blanding af alkohol og vandig ammoniak mættes med 20 gasformig ammoniak ved stuetemperatur under mekanisk omrøring. Ønskes 2-amino-2',6'-propiono-xylididet i form af et terapeutisk acceptabelt salt kan fremgangsmåden ifølge opfindelsen yderligere omfatte et trin, hvorved den normale baseform, der har den strukturelle formel I, omdannes til det ønskede salt 25 ved omsætning med den pågældende syre.The process of the present invention for synthesizing said compound I may conveniently be accomplished by saturating 2-bromo-26'-propionoxylidide in a mixture of alcohol and aqueous ammonia with 20 gaseous ammonia at room temperature with mechanical stirring. If the 2-amino-2 ', 6'-propionoxylidide is desired in the form of a therapeutically acceptable salt, the process of the invention may further comprise a step whereby the normal base form having the structural formula I is converted to the desired salt by reaction. with the acid in question.

Udtrykket "terapeutisk acceptabelt salt" kan til dette formål anses som betegnelse for et syreadditionssalt som er fysiologisk uskadeligt når det indgives i en dosis og med et interval (dvs. indgivelseshyppighed), der er effektiv for den 30 angivne terapeutiske anvendelse af moderforbindelsen. Typiske terapeutisk acceptable syreadditionssalte af 2-amino-2',6'-propiono-xylidid omfatter, men er ikke begrænset til, salte med mineralsyrer såsom saltsyre, fosforsyre eller svovlsyre og organiske syrer såsom ravsyre eller vinsyre og sulfonsyrer 35 såsom metansulfonsyre.The term "therapeutically acceptable salt" can for this purpose be considered to mean an acid addition salt which is physiologically harmless when administered at a dose and at an interval (i.e., administration frequency) effective for the therapeutic use of the parent compound indicated. Typically therapeutically acceptable acid addition salts of 2-amino-2 ', 6'-propionoxylidide include, but are not limited to, salts with mineral acids such as hydrochloric, phosphoric or sulfuric and organic acids such as succinic or tartaric and sulfonic acids such as methanesulfonic acid.

4 142843 I klinisk praksis vil de omhandlede forbindelse normalt blive indgivet oralt eller ved injektion.In clinical practice, the subject compound will usually be administered orally or by injection.

2-Amino-2',6'-propiono-xylidids evne til at undertrykke cardiale arrytmier har været eftervist i både mus og hunde.The ability of 2-Amino-2 ', 6'-propiono-xylidide to suppress cardiac arrhythmias has been demonstrated in both mice and dogs.

5 Forsøgene på mus udførtes ved en modifikation af den me tode der er beskrevet af J.W. Lawson i "Antiarrhytmic activity of some isoquinoline derivatives determined by rapid screening procedure in the mouse", J. Pharm. Exp. Therap., Vol. 160, pp. 22-31, 1968. Denne metode er baseret på den iagttagelse, at 10 når en ubedøvet, ubehandlet mus udsættes for kloroformdampe, standser dens åndedræt snart, og på dette tidspunkt viser både en elektro-cardiografisk og en visuel undersøgelse at hjerteventriklerne flimrer. Hvis musen behandles hensigtsmæssigt med kendte antiarrytmiske midler før den udsættes for kloroform, 15 ledsages åndedrætsfejlen ikke af ventrikulær flimren.The experiments on mice were performed by a modification of the method described by J.W. Lawson in "Antiarrhythmic activity of some isoquinoline derivatives determined by rapid screening procedure in the mouse", J. Pharm. Exp. Therap., Vol. 160, pp. 22-31, 1968. This method is based on the observation that when an anesthetized, untreated mouse is exposed to chloroform vapors, its breathing soon stops, and at this point both an electrocardiographic and a visual examination show that the heart ventricles flicker. If the mouse is appropriately treated with known antiarrhythmic agents before being subjected to chloroform, respiratory failure is not accompanied by ventricular flickering.

Grupper på 10 hunalbinomus af Swiss-stammen (HAM/ICR), hvis vægt var 18-25 qrforbehandledes med en dosis (ca. LD ,, U/ x dvs. den dosis der dræber 1 ud af 1000) af 2-amino-21,6'-pro-piono-xylidid i henholdsvis 10, 20, 40, 80 og/eller 160 minut-20 ter før de anbragtes i et 2000 ml bægerglas, der indeholdt vat og 50 ml kloroform. Umiddelbart efter åndedrættets ophør blev hver mus fjernet fra bægerglasset og dens brystkasse blev åbnet og dens hjerte undersøgtes for tilstedeværelse eller fraværelse af ventrikulær flimren. Den cardiale rytmes beskaffen-25 hed blev derefter fastslået ved elektrocardiogrammer. Hver gang der ikke var tydelig flimren berørtes hjertet med en pincet.Groups of 10 female albino mice of the Swiss strain (HAM / ICR) whose weight was 18-25 were pre-treated with a dose (about LD, U / x ie the dose that kills 1 in 1000) of 2-amino-21 , 6'-propionoxylidide for 10, 20, 40, 80 and / or 160 minutes, respectively, before being placed in a 2000 ml beaker containing cotton wool and 50 ml of chloroform. Immediately after cessation of breath, each mouse was removed from the beaker and its chest opened and its heart examined for the presence or absence of ventricular flickering. The nature of the cardiac rhythm was then determined by electrocardiograms. Whenever the flickering was not evident, the heart was touched with tweezers.

Hjertet blev anset som flimrende hvis der var fine rystebevægelser på ventrikeloverfladen som fortsatte i mindst 5 sekunder efter åbningen af brytshulen eller den mekaniske stimu-30 lering. Ventrikulær flimren ansås som ikke tilstedeværende i de dyr, hvor der var tydelig koordineret ventrikulær aktivitet, når en sådan fremgangsmåde blev fulgt.The heart was considered flickering if there were fine shaking movements on the ventricular surface which continued for at least 5 seconds after the opening of the rupture or mechanical stimulation. Ventricular flicker was considered not present in the animals where there was clearly coordinated ventricular activity when such a procedure was followed.

Tabel 1 viser den opnåede virkning ved indgift af li-dokain, kinidin, prokainamid og 2-amino-2',6'-propiono-xylidid! 5 142843Table 1 shows the effect obtained by administration of 1-docaine, quinidine, procainamide and 2-amino-2 ', 6'-propiono-xylidide. 5 142843

Tabel 1Table 1

Akut oral toxlcitet og antlfllmmer-virknlnger 1 mus Lægemiddel 24 timer mor- Antal mus i hver gruppe be- talitet (mg/kg) skyttet mod flimren ved LDq ^ LD[-n LDn . (Tid for indgift af lægemiddel ’ før CHCl^-påvirkning) _____ (minutter)_ ____5 10 20 40 80 160Acute oral toxicity and antiviral effects 1 mouse Drug 24 hours mother- Number of mice in each group of salivation (mg / kg) protected against flickering by LDq ^ LD [-n LDn. (Time for drug administration prior to CHCl ^ effect) _____ (minutes) _ ____5 10 20 40 80 160

KinidinX 382 348 - - 10/10 9/9 9/9KinidinX 382 348 - - 10/10 9/9 9/9

Prokain", 643 248 0/10 0/10 0/10 - amid xx;Procaine ", 643 248 0/10 0/10 0/10 - amid xx;

LidokainXx) 224 154 - 9/10 10/10 7/10 0/10 2-Amino-2', 529 382 - - 9/10 9/1010/10 9/10 6'-propiono-xylidid xx)LidocaineXx) 224 154 - 9/10 10/10 7/10 0/10 2-Amino-2 ', 529 382 - - 9/10 9/1010/10 9/10 6'-propiono-xylidide xx)

Antal mus i hver gruppe med ataksi umiddelbart før CHC1 -påvirkning JNumber of mice in each group with ataxia immediately before CHC1 influence J

(Tid for indgift af lægemidlet før CHCl^-påvirkning) 5 JO 20 4.0 80 160 n·111· min. min, min. min. min.(Time for administration of the drug prior to CHCl ^ effect) 5 JO 20 4.0 80 160 n · 111 · min. min, min. mine. mine.

x)x)

Kinidin 0/10 2/10+] 9/9+ 1 død 1 dødQuinidine 0/10 2/10 +] 9/9 + 1 dead 1 dead

Prokainamid xx^ 0/10 0/10 0/10 - -Procainamide xx ^ 0/10 0/10 0/10 - -

Lidokainxx) - 0/10 9/10 0/10 0/10 - 2-Amino-2',6'-propiono- - - 10/1010/10 8/10 5/10 xylidid xx) x) Som sulfatsalt xx) Som kloridsalt 6 142843Lidocaine x) - 0/10 9/10 0/10 0/10 - 2-Amino-2 ', 6'-propiono- - 10/1010/10 8/10 5/10 xylidide xx) x) As sulfate salt xx) As chloride salt 6

Forbindelsen 2-amino-2',6'-propiono-xylidid blev også afprøvet på hunde ved en modifikation af den metode, der er beskrevet af A.S. Harris i "Delayed Development of Ventricular Ectopic Rhythms Following Experimental Coronary Occlusions”,The compound 2-amino-2 ', 6'-propionoxylidide was also tested on dogs by a modification of the method described by A.S. Harris in "Delayed Development of Ventricular Ectopic Rhythms Following Experimental Coronary Occlusions",

Circ. Vol. 1, pp. 1318-1328, 1950. Ved denne metode bedøvedes hundene, hjertet afdækkedes og den forreste nedadgående gren af den venstre kranspulsåre afsnøredes to steder. Brystkassen blev lukket, og man lod hunden vågne op fra bedøvelsen.Circ. Vol. 1, pp. 1318-1328, 1950. By this method, the dogs were anesthetized, the heart was uncovered and the anterior descending branch of the left coronary artery was cordoned off in two places. The chest was closed and the dog was woken up from the anesthetic.

Gennem hele perioden på 2-3 dage efter et sådant kirurgisk indgreb, har elektrocardiogrammer vist tilstedeværelsen af ventrikulære arrytmier, og disse arrytmier har vist sig at kunne undertrykkes ved hjælp af kendte antiarrytmiske midler.Throughout the period of 2-3 days after such surgical intervention, electrocardiograms have shown the presence of ventricular arrhythmias and these arrhythmias have been shown to be suppressed by known antiarrhythmic agents.

(B.B. Clark og J.R. Cummings, "Arrhythmias Following Experimental Coronary Occlusion and Their Response to Drugs", Annals of New York Academy of Sciences, Vol. 65, pp. 543-551, 1956).(B.B. Clark and J.R. Cummings, "Arrhythmias Following Experimental Coronary Occlusion and Their Response to Drugs," Annals of the New York Academy of Sciences, Vol. 65, pp. 543-551, 1956).

For at afprøve den virkning, 2-amino-2',6'-propiono-xylidid har mod disse arrytmier, blev ubedøvede hunde holdt oppe af lærredsremme og behandlet intravenøst eller oralt med lægemidlet. De elektrocardiografiske, cardiovaskulære effekter og andre lægemiddelvirkninger overvågedes. Disse forsøg viste at intravenøse doser giver en tydelig undertrykkelse af de ventrikulære arrytmier uden at være ledsaget af mærkbare bivirkninger. Til andre hunde blev der givet orale doser, som også gav en tydelig undertrykkelse af de ventrikulære arrytmier.To test the effect of 2-amino-2 ', 6'-propionoxylidide on these arrhythmias, anesthetized dogs were held up by canvas straps and treated intravenously or orally with the drug. The electrocardiographic, cardiovascular effects and other drug effects were monitored. These experiments showed that intravenous doses provide a clear suppression of the ventricular arrhythmias without being accompanied by noticeable side effects. Other dogs were given oral doses which also gave a clear suppression of the ventricular arrhythmias.

Tabel 2 summerer resultaterne af oral behandling: 7 142843 m tu d d c c c. c a d u ij J]Table 2 summarizes the results of oral treatment: 7 142843 m tu d d c c c. C a d u ij J]

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H O' O' M+JOIMC+JH O 'O' M + JOIMC + J

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C c n. o m C <0 4JC c n. O m C <0 4J

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Virkningen af intravenøs infusion af lidokain og 2-amino-2',6'-propiono-xylidid i ubedøvede hunde på den første dag efter afsnøring af kranspulsåren ses i den nedenfor viste tabel 3. Doseringsplanen var: 1. time: 15 mg/kg/time; 2. time: 30 mg/ 5 kg/time; 3. time: 60 mg/kg/time. Infusionerne blev afbrudt ved det første tegn på toxicitet ud over opkastninger.The effect of intravenous infusion of lidocaine and 2-amino-2 ', 6'-propiono-xylidide in anesthetized dogs on the first day after laceration of the coronary artery is shown in Table 3. The dosing schedule was: 1. hour: 15 mg / kg /hour; 2nd hour: 30 mg / 5 kg / hour; 3rd hour: 60 mg / kg / hour. The infusions were discontinued at the first sign of toxicity in addition to vomiting.

Tabel 3Table 3

Afprøvet forbindelseTested connection

Lidokain 2-Amino-2',6 *-propiono-__________xy lidid_ 10 Antal afprøvede hunde 2 1Lidocaine 2-Amino-2 ', 6 * -propiono -__________ xy lidid_ 10 Number of dogs tested 2 1

Antal hunde, hvor der sås 2 1 antiarrytmisk virkning x'Number of dogs with 2 1 antiarrhythmic effect x

Antiarrytmiske doser (ku- 36 & 55 75 muleret (mg/kg))Anti-arrhythmic doses (cu 36 & 55 75 formulated (mg / kg))

Varighed af antiarryt-, 5 & 5 71 misk virkning (min.)xDuration of antiarrhythmic, 5 & 5 71 mical effect (min) x

Toxisk dosis (kumule- 55 & 70 81 ret, mg/kg) 15 Maksimal lægemiddelkon- 10 & 15 - centration i plasma _pg/mlToxic dose (cumulative 55 & 70 81, mg / kg) 15 Maximum drug concentration 10 & 15 - plasma concentration _pg / ml

Omtrentlig plasma t'2 xxx^ oo & oo x) Hyppigheden af unormale ventrikulære slag faldet til under 5% af det samlede antal slag.Approximate Plasma t'2 xxx ^ oo & oo x) The frequency of abnormal ventricular strokes decreased to below 5% of the total number of strokes.

xx) Tilbagevenden af 50% af de undertrykkede unormale ventrikulære slag.xx) Recurrence of 50% of suppressed abnormal ventricular strokes.

j.j.

xxx) t2 betyder halveringstiden for det indgivne lægemiddel .xxx) t2 means the half-life of the drug administered.

20 CO betyder at koncentrationen af lægemidlet i blodplasmaet forbliver nogenlunde konstant pr. tidsenhed.20 CO means that the concentration of the drug in the blood plasma remains approximately constant per day. unit of time.

Der blev udført afsnøring i nærheden af den distale rand af det venstre aurikelvedhæng. Et dobbelt ligatur skubbedes under den frigjorte pulsåre og blev skåret således at man fik to ligaturer på det samme sted på pulsåren. Det første blev 25 trukket stramt rundt om pulsåren med en 20 gauge nål, der blev lukket. Efter 30 minutter blev det andet ligatur strammet, så pulsåren lukkedes.Cut-off was performed near the distal rim of the left auricle pendant. A double ligature was pushed under the released pulmonary artery and cut so that two ligatures were obtained at the same location on the pulmonary artery. The first was 25 pulled tight around the pulmonary artery with a 20 gauge needle being closed. After 30 minutes, the second ligature was tightened so that the pulmonary artery closed.

9 1Λ28Λ39 1Λ28Λ3

Forbindelsen 2-amino-2',6'-propiono-xylidid udviser uventede antiarrytmiske virkninger. Den har en meget svag lokalan-aestetisk virkning sammenlignet med lidokain, der er et kendt anæstetisk og antiarrytmisk lægemiddel. Til eftervisning af 5 dette sammenlignedes virkningen på en frøs ischiasnerve af opløsninger på 20 ml af 2-amino-261-propiono-xylidid og lidokain in vitro i overensstemmelse med den metode, der angives af Camougis og Takman, i "Nerve and Nervemuscle Preparations (As Applied to Local Anaesthetics)", Kapitel 1 i Methods of 10 Pharmacology, A. Schwartz ed., Appleton-Century Crofts, New York 1970. Det viste sig at lidokainopløsningen efter 5 minutter blokerer hoftenervens aktionspotentiale i et omfang på 78% af det normale potentiale, mens den ved fremgangsmåden ifølge opfindelsen fremstillede forbindelse overhovedet ikke bloke-15 rer aktionspotentialet selv efter 96 minutters påvirkning af hoftenerven med opløsningen.The compound 2-amino-2 ', 6'-propionoxylidide exhibits unexpected antiarrhythmic effects. It has a very weak local anesthetic effect compared to lidocaine, which is a known anesthetic and antiarrhythmic drug. To demonstrate this, the effect on a sciatica nerve of solutions of 20 ml of 2-amino-261-propionoxylidide and lidocaine in vitro was compared according to the method set forth by Camougis and Takman in "Nerve and Nervemuscle Preparations ( As Applied to Local Anaesthetics) ", Chapter 1 of Methods of 10 Pharmacology, A. Schwartz, ed., Appleton-Century Crofts, New York 1970. After 5 minutes, lidocaine solution was found to block the action potential of the hip nerve to an extent of 78% of that. normal potential, while the compound made by the process of the invention does not block the action potential at all even after 96 minutes of impacting the hip nerve with the solution.

Til trods for den almene velunderbyggede hidtidige lære om at antiarrytmisk virkning og lokalbedøvende virkning er nært forbundne og at primære aminer er meget svagere lokalbedøvel-20 sesmidler end de tilsvarende sekundære aminer, udviser det svage lokalbedøvelsesmiddel, 2-amino-21,6'-propiono-xylidid, kraftige antiarrytmiske egenskaber som er af lang virkningsvarighed. A.P. Truant og B. Takman, "Local Anesthetics", Drills, Pharmacology and Medicine, J.R. DiPalma, ed., McGraw-Hill 25 Book Co., New York, N.Y., 1965 og F.F. Doerge, "Local Anesthetic Agents", Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th Ed., ved C.O. Wilson m.fl., Lippincott, Philadelphia, Pa,, pp. 597-598, 1966.Despite the general well-established past teachings that antiarrhythmic and local anesthetic effects are closely related and that primary amines are much weaker local anesthetics than the corresponding secondary amines, the weak local anesthetic, 2-amino-21,6'-propiono, exhibits -xylidide, powerful antiarrhythmic properties of long duration of action. A.P. Truant and B. Takman, "Local Anesthetics," Drills, Pharmacology and Medicine, J.R. DiPalma, ed., McGraw-Hill 25 Book Co., New York, N.Y., 1965 and F.F. Doerge, "Local Anesthetic Agents," Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th Ed., By C.O. Wilson et al., Lippincott, Philadelphia, Pa., Pp. 597-598, 1966.

Der er foretaget en sammenligning mellem den tidligere 30 nævnte kendte forbindelse N-(N-dimetylalanyl)-2,6-dimetyl-anilin (A) og 2-amino-2',6'-propiono-xylidid (B). Ved denne sammenligning undersøgtes forbindelsernes beskyttende virkning mod kloroformfremkaldt hjerteflimmer hos mus ifølge den metode, der er beskrevet ovenfor i forbindelse med de i tabel 1 viste 35 resultater. Resultaterne fremgår af tabel 4.A comparison has been made between the aforementioned known compound N- (N-dimethylalanyl) -2,6-dimethyl-aniline (A) and 2-amino-2 ', 6'-propionoxylidide (B). In this comparison, the protective effect of the compounds against chloroform-induced cardiac fibrillation in mice was investigated according to the method described above for the results shown in Table 1. The results are shown in Table 4.

10 14284310 142843

Tabel 4Table 4

Akut oral toxicitet og anti-flimmereffekt hos mus /-CH3 0 CH, .»1Acute oral toxicity and anti-flicker effect in mice / -CH3 0 CH1. »1

II I 3 /RII I 3 / R

\=/ \h2 \ch3 24 timers Andelen af mus som beskyttedes mod mortalitet flimren ved LDo,l (Tid fra prøveforbindelsen indgives ____før dyrene udsættes for kloroform) 1 2 5 R R LD__ LD_ , 5 min. 10 min. 20 min. 40 min. 80 min.\ = / \ h2 \ ch3 24 hours Percentage of mice protected against mortality flickering by LDo, l (Time from test compound is administered ____ before animals are exposed to chloroform) 1 2 5 R R LD__ LD_, 5 min. 10 min. 20 min. 40 min. 80 min.

5U U, 1 CH3 CH3 315 61 20% 0% 20% Η H 529 382 - 90% 90% 100% ;_ _ III ________5U U, 1 CH3 CH3 315 61 20% 0% 20% Η H 529 382 - 90% 90% 100%; _ _ III ________

Det fremgår af tabellen at forbindelse A har en meget svag beskyttende virkning samtidig med at den er mere toxisk 10 end forbindelse B. Forbindelse B har en tydeligt større beskyttende virkning som desuden er af betydeligt længere varighed.It can be seen from the table that Compound A has a very weak protective effect while being more toxic than Compound B. Compound B has a significantly greater protective effect which is also of considerably longer duration.

Disse resultater underbygges af en sammenligning af den farmakologiske halveringstid beregnet på blodkoncentrationer-15 ne efter oral indgift af de to forbindelser hos hunde.These results are supported by a comparison of the pharmacological half-life based on blood concentrations after oral administration of the two compounds in dogs.

halveringstid (middelværdi af to bestemmelser_ forbindelse A 2 4/10 timer forbindelse B 4 7/10 timerhalf-life (mean of two determinations_ compound A 2 4/10 hours compound B 4 7/10 hours

Det fremgår tydeligt af de ovenfor viste forsøgsresul-20 tater, at den ved fremgangsmåden ifølge opfindelsen fremstillede forbindelse B har en særlig fordelagtig virkning i forhold til den kendte og strukturelt nært beslægtede forbindelse A.It is clear from the test results shown above that the compound B prepared by the process according to the invention has a particularly advantageous effect over the known and structurally closely related compound A.

11 14284311 142843

Ved fremgangsmåden ifølge opfindelsen syntetiseres 2-amino-2',6'-propiono-xylidid ved omsætning af det tilsvarende 2-klor-, 2-brom- eller 2-jod-2',6'-propiono-xylidid med ammoniak i alkoholisk/vandig opløsning eller alkoholisk opløsning.In the process of the invention, 2-amino-2 ', 6'-propiono-xylidide is synthesized by reacting the corresponding 2-chloro, 2-bromo or 2-iodo-2', 6'-propiono-xylidide with ammonia in alcoholic / aqueous solution or alcoholic solution.

5 Ammoniakken tilsættes som gas enten kontinuert eller med mellemrum ved lav temperatur. En blanding af ammoniumhydroxyd, alkohol og gasformigt ammoniak kan også anvendes. Reaktanterne kan holdes på stuetemperatur eller højere temperaturer i en lukket beholder. Hvis der anvendes stuetemperatur omrøres 10 blandingen i 4-9 dage.5 The ammonia is added as gas either continuously or at low temperature intervals. A mixture of ammonium hydroxide, alcohol and gaseous ammonia may also be used. The reactants can be kept at room temperature or higher in a closed container. If room temperature is used, the mixture is stirred for 4-9 days.

Fremgangsmåden ifølge opfindelsen forklares nærmere i følgende eksempel:The process according to the invention is further explained in the following example:

Eksempel 2-Amino-21,61-propiono-xylidid 15 Forbindelsen 2-amino-2',6'-propiono-xylidid syntetise redes ved at en suspension af 50 g (0,195 mol) 2-brom-2',6'-propiono-xylidid i en blanding af 500 ml 95%'s alkohol og 400 ml koncentreret ammoniakvand mættedes med gasformigt ammoniak ved stuetemperatur. Mætningen udførtes under mekanisk om-20 røring. Efter 25 timer mættedes blandingen atter med ammoniakgas. Omrøringen ved stuetemperatur fortsattes i en samlet periode på 116 timer, og på dette tidspunkt blev der udtaget en prøve. Gaskromatografisk analyse viste at ca. 95% af bromforbindelsen var blevet omdannet til det ønskede produkt. Opløs-25 ningsmidlerne afdampedes i vakuum og remanensen optoges i 80 ml 3M saltsyre. Efter tilsætning af 220 ml vand filtreredes det uopløselige materiale fra og vaskedes med 100 ml vand, hvorpå det tørredes. Det uopløselige materiale vejede 9,5 g og var hovedsageligt uomsat bromforbindelse. Filtratet omsattes med 30 50 ml 7M NaOH, ekstraheredes 3 gange med metylenklorid (50 ml + 2 x 25 ml) og tørredes over kaliumkarbonat, hvorpå det inddampedes. Udbyttet af remanensen var 26,8 g svarende til 71,4% af det teoretiske udbytte. Denne remanens var en farveløs størknende olie som opløstes i 200 ml kloroform. Hydrogenklorid 35 bobledes igennem indtil en prøve af opløsningen viste sur reaktion på vådt indikatorpapir. Der vandtes et bundfald som opsamledes ved filtrering. Det vaskedes med kloroform og tørredes.Example 2-Amino-21,61-propiono-xylidide The compound 2-amino-2 ', 6'-propiono-xylidide is synthesized by a suspension of 50 g (0.195 mol) of 2-bromo-2', 6'- propionoxylidide in a mixture of 500 ml of 95% alcohol and 400 ml of concentrated ammonia water was saturated with gaseous ammonia at room temperature. The saturation was performed under mechanical stirring. After 25 hours, the mixture was saturated again with ammonia gas. Stirring at room temperature was continued for a total period of 116 hours, at which point a sample was taken. Gas chromatographic analysis showed that approx. 95% of the bromine compound had been converted to the desired product. The solvents were evaporated in vacuo and the residue was taken up in 80 ml of 3M hydrochloric acid. After adding 220 ml of water, the insoluble material was filtered off and washed with 100 ml of water and then dried. The insoluble material weighed 9.5 g and was essentially unreacted bromine compound. The filtrate was reacted with 30 ml of 7M NaOH, extracted 3 times with methylene chloride (50 ml + 2 x 25 ml) and dried over potassium carbonate and then evaporated. The yield of the residue was 26.8 g, corresponding to 71.4% of the theoretical yield. This residue was a colorless solidifying oil which was dissolved in 200 ml of chloroform. Hydrogen chloride 35 was bubbled through until a sample of the solution showed acidic reaction on wet indicator paper. A precipitate was obtained which was collected by filtration. It was washed with chloroform and dried.