DK146063B - METHOD OF ANALOGUE FOR THE PREPARATION OF METHYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF METHYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. Download PDFInfo
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- DK146063B DK146063B DK244677AA DK244677A DK146063B DK 146063 B DK146063 B DK 146063B DK 244677A A DK244677A A DK 244677AA DK 244677 A DK244677 A DK 244677A DK 146063 B DK146063 B DK 146063B
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- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Description
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Den foreliggende opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte methylaminderivater med den almene formel n-C3H7 ΛThe present invention relates to an analogous process for the preparation of novel methylamine derivatives of the general formula n-C3H7 Λ
R--C-N IR - C-N I
/ \ n-C^H^ R2 5 hvori R betyder n-propy1, isopropyl, isobutyl eller allyl, R., betyder hydrogen, methyl eller propargyl, og R2 betyder methyl eller propargyl, eller farmaceutisk acceptable syreadditionssalte deraf, dog ikke N,N-dimethyl-l,l-di-n-propyl-n-butylamin, hvilken fremgangsmåde er ejendommelig ved, at en, for-10 bindelse med den almene formel n-C,H7 \wherein R is n-propyl, isopropyl, isobutyl or allyl, R is hydrogen, methyl or propargyl, and R 2 is methyl or propargyl, or pharmaceutically acceptable acid addition salts thereof, but not N, N- dimethyl-1,1-di-n-propyl-n-butylamine, which is characterized in that a compound of the general formula nC, H7
R-C-NHR- IIR-C-NHR-II
/ n-C3H7 hvori R har den ovenfor angivne betydning, og betyder hydrogen, methyl eller propargyl, eller et syreadditionssalt deraf opvarmes i nærværelse af et basisk middel med en pas-15 sende mængde af et halogenid med den almene formelwherein n is as defined above and means hydrogen, methyl or propargyl, or an acid addition salt thereof is heated in the presence of a basic agent with a suitable amount of a halide of the general formula
R4X IIIR4X III
hvori R^ betyder methyl eller propargyl, og X betyder chlor, brom eller iod, eventuelt i nærværelse af et opløsningsmiddel, hvorpå det dannede methylaminderivat med formlen I even-20 tuelt omdannes til et farmaceutisk acceptabelt syreadditionssalt med en organisk eller uorganisk syre.wherein R 1 is methyl or propargyl, and X is chlorine, bromine or iodine, optionally in the presence of a solvent, whereupon the formed methylamine derivative of formula I is optionally converted to a pharmaceutically acceptable acid addition salt with an organic or inorganic acid.
De farmaceutisk acceptable syreadditionssalte af forbindelserne med formlen I er sådanne af uorganiske syrer, f.eks. saltsyre, eller af organiske syrer, i hvilke den frie carb-25 oxylgruppe er bundet til en mættet eller umættet aliphatisk gruppe, en aromatisk gruppe eller en aralkylgruppe, der eventuelt kan indeholde en anden carboxylgruppe, f.eks. fumarsyre.The pharmaceutically acceptable acid addition salts of the compounds of formula I are those of inorganic acids, e.g. hydrochloric acid, or of organic acids in which the free carboxyl group is bonded to a saturated or unsaturated aliphatic group, an aromatic group or an aralkyl group which may optionally contain another carboxyl group, e.g. fumaric acid.
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Som nærmere forklaret i det følgende har methylaminderiva-terne med formlen I og deres farmaceutisk acceptable syreadditionssalte farmakologiske egenskaber, der må gøre dem særligt nyttige til behandling af Parkinsons sygdom og til 5 korrektion af ekstrapyramidale forstyrrelser, der er fremkaldt af neuroleptika.As further explained below, the methylamine derivatives of formula I and their pharmaceutically acceptable acid addition salts have pharmacological properties which may render them particularly useful in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by neuroleptics.
Man kan behandle Parkinsons sygdom og korrigere ekstrapyramidale forstyrrelser fremkaldt af neuroleptika ved at administrere en virksom dosis af mindst én forbindelse med form-10 len I eller et farmaceutisk acceptabelt syreadditionssalt deraf til den angrebne patient.One can treat Parkinson's disease and correct extrapyramidal disorders caused by neuroleptics by administering an effective dose of at least one compound of Formula I or a pharmaceutically acceptable acid addition salt thereof to the affected patient.
Den daglige dosis ligger fortrinsvis mellem 10 og 60 mg aktivt stof til et menneske med en legemsvægt på ca. 60 kg.The daily dose is preferably between 10 and 60 mg of active ingredient in a human with a body weight of approx. 60 kg.
Forbindelserne med formlen I, hvori og R2 hver for sig 15 betyder methyl, er omfattet af den i USA-patentskrift nr.The compounds of formula I, in which and R 2 independently are methyl, are encompassed in the U.S. Pat.
. 3.067.101 anførte almene formel, der omfatter et meget stort antal forbindelser, men de er ikke specielt nævnt i ovennævnte patentskrift, og de er således ikke kendt derfra.. 3,067,101 to the general formula which encompasses a very large number of compounds, but they are not specifically mentioned in the above-mentioned patent, and thus are not known therefrom.
20 Ved omsætning af forbindelsen II med forbindelsen III kan det basiske middel f.eks. være natriumhydrogencarbonat, og syreadditionssaltet af udgangsforbindelsen er f.eks. hydro-chloridet. Som opløsningsmiddel kan anvendes ethanol.By reacting compound II with compound III, the basic agent may e.g. be sodium bicarbonate and the acid addition salt of the starting compound is e.g. the hydrochloride. Ethanol can be used as the solvent.
Når man ønsker at opnå en forbindelse med formlen I med to 25 ens substituenter på nitrogenatomet, omsættes den tilsvarende forbindelse med formlen II, dvs. en forbindelse med formlen II, hvori R har den ønskede betydning, og R^ betyder hydrogen, i overensstemmelse med kendte kemiske fremgangsmåder således, at to molækvivalenter af halogenidet 30 med formlen III reagerer med ét molækvivalent af forbindelsen II.When one wishes to obtain a compound of formula I with two identical substituents on the nitrogen atom, the corresponding compound of formula II, i.e. a compound of formula II wherein R is the desired meaning and R 1 is hydrogen, in accordance with known chemical methods such that two molar equivalents of the halide 30 of formula III react with one molar equivalent of compound II.
3 146063 Når man derimod ønsker at opnå en forbindelse med formlen I med et hydrogenatom på nitrogenatomet, omsættes den tilsvarende forbindelse med formlen II, dvs, en forbindelse med formlen II, hvori R har den ønskede betydning, og R^ 5 betyder hydrogen, således at ét molækvivalent af halogenidet med formlen III reagerer med ét molækvivalent af forbindelsen med formlen II.By contrast, when one wishes to obtain a compound of formula I with a hydrogen atom on the nitrogen atom, the corresponding compound of formula II is reacted, i.e., a compound of formula II wherein R has the desired meaning and R 5 represents hydrogen, thus that one mole equivalent of the halide of formula III reacts with one mole equivalent of the compound of formula II.
Det er kendt, at man ved fremstilling af en forbindelse med 10 formlen I, som er monosubstitueret ved nitrogenatomet, får en blanding, der udover den ønskede monosubstituerede forbindelse indeholder en vis mængde af en tilsvarende ved nitrogenatomet disubstitueret forbindelse med formlen I, selv om man anvender de ovenfor angivne molækvivalenter.It is known that in the preparation of a compound of formula I, which is monosubstituted by the nitrogen atom, a mixture containing, in addition to the desired monosubstituted compound, a certain amount of a correspondingly nitrogen-substituted compound of formula I is obtained. uses the above molar equivalents.
15 Tilsvarende dannes en vis mængde af den ved nitrogenatomet monosubstituerede forbindelse, når man fremstiller den tilsvarende disubstituerede forbindelse.Correspondingly, a certain amount of the nitrogen atom monosubstituted compound is formed when preparing the corresponding disubstituted compound.
Sådanne blandinger af mono- og disubstituerede derivater kan adskilles efter kendt teknik, f.eks. ved fraktioneret 20 destillation af reaktionsblandingen eller ved fraktioneret krystallisation af deres salte.Such mixtures of mono- and disubstituted derivatives can be separated by known techniques, e.g. by fractional distillation of the reaction mixture or by fractional crystallization of their salts.
Blandt forbindelserne med formlen II er sådanne, hvori R^ betyder hydrogen, kendte forbindelser, der tillige med en fremgangsmåde til deres fremstilling er beskrevet i britisk 25 patentskrift nr. 1.467.739.Among the compounds of formula II are those in which R 1 represents hydrogen, known compounds which are also described in a process for their preparation in British Patent Specification No. 1,467,739.
De øvrige forbindelser med formlen II, nemlig sådanne, hvori R3 betyder methyl eller propargyl, falder ind under forbindelserne med formlen I, hvis fremstilling er beskrevet ovenfor.The other compounds of formula II, namely those wherein R 3 is methyl or propargyl, fall into the compounds of formula I, the preparation of which is described above.
30 Som tidligere anført har de omhandlede methylaminderivater værdifulde farmakologiske egenskaber, der gør dem nyttige i human- og veterinærterapien.As previously stated, the methylamine derivatives in question have valuable pharmacological properties that make them useful in human and veterinary therapy.
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Især har de omhandlede forbindelser central-noradrenerge og central-dopaminerge egenskaber. Disse sidste egenskaber viser sig ved en inhiberende virkning på reserpin-induceret og neuroleptisk induceret katatoni og katalepsi.In particular, the compounds of this invention have central-noradrenergic and central-dopaminergic properties. These latter properties are evidenced by an inhibitory effect on reserpine-induced and neuroleptic-induced catatonia and catalepsy.
5 I doser, der fuldstændigt Undertrykker neuroleptisk induceret katatoni og katalepsi, påvirker de omhandlede forbindelser endvidere ikke neuroleptikas antiamphetamin-virk-ning på rotter og anti-apomorphin-virkning på hunde. Uanset dosisstørrelse har omhandlede forbindelser endvidere 10 ikke emetisk virkning på hunde, og de er ikke cholinolyti-ske midler.Furthermore, in doses that completely suppress neuroleptic-induced catatonia and catalepsy, the compounds of this invention do not affect the antiolhetamine action of neuroleptics in rats and anti-apomorphine action in dogs. Furthermore, regardless of dose size, the compounds of this invention have no emetic effect on dogs and are not cholinolytic agents.
Disse farmakologiske egenskaber taget under ét gør forbindelserne med formlen I nyttige til behandlingen af Parkinsons sygdom samt til korrigering af ekstrapyramidale for-15 styrrelser fremkaldt af neuroleptika.These pharmacological properties taken together make the compounds of formula I useful for the treatment of Parkinson's disease and for the correction of extrapyramidal disorders caused by neuroleptics.
Sådanne forbindelser, der er trisubstitueret på methylamin-delen, men usubstitueret på nitrogenatomet, er allerede kendte for at udvise central-noradrenerge og central-dopaminerge egenskaber, der gør dem nyttige til behandlingen af 20 Parkinsons sygdom og til korrigering af ekstrapyramidale forstyrrelser fremkaldt af neuroleptika.Such compounds which are trisubstituted on the methylamine moiety but unsubstituted on the nitrogen atom are already known to exhibit central noradrenergic and central dopaminergic properties which make them useful in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by neuroleptics. .
Disse forbindelser er beskrevet i britisk patentskrift nr. 1.467.739.These compounds are described in British Patent Specification No. 1,467,739.
Det har endvidere vist sig, at forbindelser, der er disub-25 stitueret på methylamindelen men usubstitueret på nitrogenatomet, såsom 1-n-propyl-n-butylamin, også har de nødvendige egenskaber til at blive anvendt som anti-Parkinsonske midler.Furthermore, it has been found that compounds disubstituted on the methylamine moiety but unsubstituted on the nitrogen atom, such as 1-n-propyl-n-butylamine, also have the necessary properties to be used as anti-Parkinson's agents.
Imidlertid har de disubstituerede og trisubstituerede 30 methylaminderivater, der ikke er substitueret på nitrogenatomet, inhiberende virkning på monoaminoxidase i varierende grad.However, the disubstituted and trisubstituted methylamine derivatives that are not substituted on the nitrogen atom have varying degrees of inhibitory effect on monoamine oxidase.
5 146063 I klinisk anvendelse viser denne inhiberende virkning sig ved uønskede bivirkninger, såsom tachycardi, paroxystisk hypotension og hypertension.In clinical use, this inhibitory effect is shown by undesirable side effects such as tachycardia, paroxystic hypotension and hypertension.
Det har imidlertid overraskende vist sig, at de omhandlede 5 forbindelser har en meget svagere eller slet ingen inhiberende virkning på monoaminoxidase end de ovennævnte kendte di- og trisubstituerede methylaminderivater i samme koncentration.However, it has surprisingly been found that the compounds of the present invention have a much weaker or no inhibitory effect on monoamine oxidase than the above known di- and trisubstituted methylamine derivatives at the same concentration.
Denne fuldstændigt uventede fordel ved de omhandlede N-sub-10 stituerede methylaminderivater i forhold til de kendte di-og trisubstituerede methylaminderivater, der ikke er substitueret på nitrogenatomet, bibringer de omhandlede forbindelser større nytteværdi end de på nitrogenatomet usub-stituerede derivater.This completely unexpected advantage of the N-substituted methylamine derivatives of the present invention over the known di- and trisubstituted methylamine derivatives which are not substituted on the nitrogen atom gives the compounds of this invention greater utility than the unsubstituted derivatives on the nitrogen atom.
15 De omhandlede forbindelser er også mere fordelagtige end amantadin, dvs. 1-amino-adamantan, der er en forbindelse, som anvendes i udstrakt grad til behandling af Parkinsons sygdom.The present compounds are also more advantageous than amantadine, ie. 1-amino-adamantane, a compound widely used to treat Parkinson's disease.
Selv om det farmakologiske spektrum af de omhandlede forbin-20 delser er meget lig spektret af amantadin, har farmakologiske forsøg udført med de omhandlede forbindelser og amantadin vist udprægede forskelle. Ved sammenligning af doserne af de omhandlede forbindelser og af amantadin for en bestemt virkningsgrad har det f.eks. vist sig, at den virk-25 somme dosis altid er forholdsmæssigt fjernere fra den toksiske dosis ved de omhandlede forbindelser end ved amantadin. Med andre ord er sikkerhedsmargenen for de omhandlede forbindelser større end for amantadin.Although the pharmacological spectrum of the compounds of the present invention is very similar to the spectrum of amantadine, pharmacological tests performed with the compounds of the present invention and amantadine have shown marked differences. When comparing the doses of the compounds of the present invention and of amantadine for a particular efficiency, it has e.g. It has been found that the effective dose is always proportionately more distant from the toxic dose of the compounds of the present invention than of amantadine. In other words, the safety margin of the compounds of the present invention is greater than that of amantadine.
Udviklingen af nye anti-Parkinsonske midler er yderst vig-30 tig, da behandlingen er af lang varighed, og skiftende anvendelse af forskellige produkter er nødvendig.The development of new anti-Parkinson's agents is extremely important as the treatment is of long duration and changing use of different products is necessary.
Ud fra dette synspunkt er de omhandlede forbindelser værdifulde suppleringer til udvalget af de til rådighed stående 6 146063 anti-Parkinsonske midler, idet der for øjeblikket ikke findes noget ideelt middel til behandling af denne sygdom, som forklaret ovenfor.From this point of view, the compounds of the present invention are valuable supplements to the selection of the available anti-Parkinson's agents, as there is currently no ideal remedy for the treatment of this disease, as explained above.
De omhandlede N-substituerede og Ν,Ν-disubstituerede deriva-5 ter, der har vist de mest værdifulde egenskaber som anti-Parkinsonske midler, er N-methyl-1,1-di-n-propyl-n-butyl-amin i form af den frie base eller i form af et farmaceutisk acceptabelt syreadditionssalt , såsom hydrochloridet eller fumaratet, og N,N-dimethyl-l,l-di-n-propyl-n-butylamin 10 i form af et farmaceutisk acceptabelt syreadditionssalt, f.eks. hydrochloridet.The present N-substituted and Ν, dis-disubstituted derivatives which have shown the most valuable properties as anti-Parkinson's agents are N-methyl-1,1-di-n-propyl-n-butylamine in in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt, such as the hydrochloride or fumarate, and N, N-dimethyl-1,1-di-n-propyl-n-butylamine 10 in the form of a pharmaceutically acceptable acid addition salt, f. eg. hydrochloride.
De omhandlede forbindelsers central-dopaminerge virkning er for nogle af disse forbindelser anført nedenfor sammen med virkningen af amantadin. Forbindelserne blev undersøgt i 15 form af hydrochloriderne. Det var hydrochloriderne af følgende forbindelser.The central dopaminergic activity of the compounds of the present invention is listed below for some of these compounds together with the action of amantadine. The compounds were tested in the form of the hydrochlorides. It was the hydrochlorides of the following compounds.
N-methyl-1,1-di-n-propyl-n-butylamin (forbindelse 1) Ν,Ν-dimethyl-1,1-di-n-propyl-n-butylamin (forbindelse 2) N-methyl-l-n-propyl-l-isopropyl-n-butylamin (forbindelse 3) 20 N-methyl-l-n-propyl-l-isobutyl-n-butylamin (forbindelse 4) N-methyl-l-n-propyl-l-allyl-n-butylamin (forbindelse 5) N-propargy 1-1 > 1-di-n-p'ropyl-n-butylamin (forbindelse 6) N,N-dimethyl-l-n-propyl-l-isobutyl-n-butylamin (forbindelse 7) N,N-dipropårgyl-l,1-di-n-propyl-n-butylamin (forbindelse 8).N-methyl-1,1-di-n-propyl-n-butylamine (compound 1) Ν, Ν-dimethyl-1,1-di-n-propyl-n-butylamine (compound 2) N-methyl-1 propyl-1-isopropyl-n-butylamine (compound 3) N-methyl-1n-propyl-1-isobutyl-n-butylamine (compound 4) N-methyl-1n-propyl-1-allyl-n-butylamine (compound) 5) N-Propargy 1-1> 1-di-n-propyl-n-butylamine (compound 6) N, N-dimethyl-1n-propyl-1-isobutyl-n-butylamine (compound 7) N, N -dipropyrgyl-1,1-di-n-propyl-n-butylamine (Compound 8).
25 I de følgende forsøg refererer forbindelsens nummer til hydrochloridet.In the following experiments, the compound number refers to the hydrochloride.
I. Inhibering af reserpin-induceret og neuroleptisk indu- ceret katatoni (dopaminerge egenskaber)_ 1. Inhibering af reserpin-induceret katatoni.I. Inhibition of Reserpine-Induced and Neuroleptic Induced Catatonia (dopaminergic properties) 1. Inhibition of reserpine-induced catatonia.
Det til undersøgelsen anvendte forsøg svarer til forsøget beskrevet i britisk patentskrift nr. 1.467.739.The test used for the study is similar to the test described in British Patent Specification No. 1,467,739.
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De med de ovenfor anførte omhandlede forbindelser og aman-tadin opnåede resultater er anført nedenfor i tabel I. Resultaterne er udtrykt efter samme pointsystem, fra 0 til 4, som angivet i ovennævnte britiske patentskrift.The results obtained with the above-mentioned compounds and amanadadine are given below in Table I. The results are expressed according to the same scoring system, from 0 to 4, as stated in the above-mentioned British patent.
5 Tabel ITable I
Forbin- Administreret Inhibering af reserpininduceret delse dosis i mq/kg katatoni:_ 16 4 2 6 4 10 3 6 4 4 6,5 3 5 5 2 6 6 1 7 6,5 3 15 8 15 2Combine-Administered Inhibition of Reserpine Induced Dose Dose in Mq / kg Catatonia: _ 16 4 2 6 4 10 3 6 4 4 6.5 3 5 5 2 6 6 1 7 6.5 3 15 8 15 2
Amantadin 100 4 2. Inhibering af neuroleptisk induceret katatoni.Amantadine 100 4 2. Inhibition of neuroleptic induced catatonia.
Det til denne undersøgelse anvendte forsøg svarer til forsø-20 get beskrevet i britisk patentskrift nr. 1.467.739.The test used for this study is similar to the test described in British Patent Specification No. 1,467,739.
De med de ovenfor anførte forbindelser samt med amantadin opnåede resultater er anført i den følgende tabel II.The results obtained with the above compounds as well as with amantadine are given in the following Table II.
Pointsystemet er det samme som anvendt ovenfor i tabel I.The point system is the same as used above in Table I.
Tabel IITable II
25 Forbin- Administreret Inhibering af neuroleptisk delse_dosis i mg/kg induceret katatoni_ 16 3 2 6 4 3 6 3 30 4 6,5 4 5 5 2 6 6 4 7 6,5 225 Combine-Administered Inhibition of Neuroleptic Disorder_dose in mg / kg induced catatonia_ 16 3 2 6 4 3 6 3 30 4 6.5 4 5 5 2 6 6 4 7 6.5 2
Amantadin_100_4_ 8 146063Amantadin_100_4_ 8 146063
Supplerende forsøg har vist, at forbindelse 2 i en dosis så lav som 3 mg/kg har et inhiberingsindeks for neuroleptisk induceret katatoni på 2.Complementary experiments have shown that compound 2 at a dose as low as 3 mg / kg has an inhibition index of neuroleptic induced catatonia of 2.
II. Akut toksicitet.II. Acute toxicity.
5 Den akutte toksicitet LD^q bestemtes på mus ad oral vej ved anvendelse af samme metode som beskrevet i britisk patentskrift nr. 1.467.739. Følgende resultater blev opnået med de omhandlede forbindelser og amantadin:The acute toxicity LD 2 was determined on mice by oral route using the same method as described in British Patent Specification No. 1,467,739. The following results were obtained with the subject compounds and amantadine:
Forbindelse LD50 * m9/kg 10 1 100 .Compound LD50 * m9 / kg 10 1 100.
3 >150 5 170 6 >150 7 110 15 8 >1503> 150 5 170 6> 150 7 110 15 8> 150
Amantadin 1050Amantadine 1050
Man sammenlignede indekset LD50/ED20_3Q for de omhandlede forbindelser med det tilsvarende indeks for amantadin.The LD50 / ED20_3Q index of the compounds in question was compared with the corresponding index of amantadine.
I dette indeks betyder ED20-30 ^en e^^e^t;*-ve dosis til opnå-20 else af 20 til 30%'s inhibering af katatoni (udtrykt ved den første værdi i tabel I og II). Følgende resultat fandtes:In this index, ED20-30 ^ means a dose of 20% to achieve 20 to 30% of catatonia inhibition (expressed by the first value in Tables I and II). The following results were found:
Forbindelse Indeks 6 >25Connection Index 6> 25
Amantadin 21 25 Dette resultat viser, at den omhandlede forbindelse er mere fordelagtig end amantadin, fordi den har en større sikkerhedsmargen.Amantadine 21 25 This result shows that the compound in question is more advantageous than amantadine because it has a greater safety margin.
Ligeledes blev indekset LD^q/ED^qq bestemt for de omhandlede forbindelser og amantadin.Likewise, the LD ^ q / ED ^ qq index was determined for the compounds and amantadine.
30 Der blev opnået følgende resultater: 9 146063The following results were obtained: 9 146063
Forbindelse Indeks 1 16,5 3 >25Compound Index 1 16.5 3> 25
Amantadin 10 5 Disse resultater viser igen, at de omhandlede forbindelser har en større sikkerhedsmargen end amantadin.Amantadine 10 5 These results again show that the compounds of the present invention have a greater safety margin than amantadine.
III. Bestemmelse af inhiberingen af monoaminoxidase.III. Determination of the inhibition of monoamine oxidase.
Til denne undersøgelse udførtes følgende forsøg:For this study, the following experiments were performed:
To rotter på henholdsvis 190 og 200 g blev aflivet ved hals-10 hugning. Leveren blev fjernet hurtigt og blev skåret i hyper-tonisk medium og banket. Homogenisatet blev renset ved fraktionscentrifugering og mitochondrias-fraktionen opsamlet.Two rats weighing 190 and 200 g were sacrificed by neck-10 chopping. The liver was quickly removed and cut into hyper-tonic medium and knocked. The homogenate was purified by fractionation centrifugation and the mitochondria fraction collected.
Den undersøgte forbindelses inhibering af monooxidase måltes ved polarografi.The inhibition of monooxidase by the compound studied was measured by polarography.
15 I en målecelle kom man følgende opløsninger: a) 1,1 ml af en 0,1 molær phosphatpufferopløsning (pH 7,4), til hvilken var sat en 0,005 molær opløsning af kaliumcyanid, b) 0,01 ml af en 0,5 molær vandig opløsning af den undersøgte forbindelse (slutkoncentrationen af produktet i cel- 20 len: 0,00333 molær) og c) 0,1 ml af den tidligere fremstillede mitochondrias-suspension, dvs. 12,5 mg protein.In a measuring cell, the following solutions were obtained: a) 1.1 ml of a 0.1 molar phosphate buffer solution (pH 7.4) to which was added a 0.005 molar solution of potassium cyanide, b) 0.01 ml of a 0, 5 molar aqueous solution of the tested compound (final concentration of the product in the cell: 0.00333 molar) and c) 0.1 ml of the previously prepared mitochondria suspension, i.e. 12.5 mg of protein.
Tre minutter efter denne arbejdsgang startedes omsætningen ved tilsætning af 0,2 ml af en 0,05 molær opløsning af 25 serotonin-kreatinsulfat i phosphatpufferopløsning, således at slutkoncentrationen af amin i cellen var 0,00666 molær.Three minutes after this operation, the reaction was started by adding 0.2 ml of a 0.05 molar solution of 25 serotonin creatine sulfate in phosphate buffer solution so that the final concentration of amine in the cell was 0.00666 molar.
Titer i mitochondrias beregnedes ifølge biuretmetoden, idet oksealbumin anvendtes som proteinreference.Titers in mitochondria were calculated according to the biuret method, using oxalbumin as a protein reference.
Lignende forsøg udførtes også med 0,02, 0,04, 0,06, 0,08 30 og 0,10 ml af den 0,5 molære opløsning af den undersøgte forbindelse.Similar experiments were also performed with 0.02, 0.04, 0.06, 0.08 and 0.10 ml of the 0.5 molar solution of the compound under study.
ίο 148063ίο 148063
De følgende resultater viser den procentuelle inhibering af monoaminoxidase af en omhandlet forbindelse i sammenligning med inhiberingsvirkningen af to methylaminderivater, der er usubstitueret på nitrogenatomet- De to derivater under-5 søgtes under samme betingelser som den omhandlede forbindelse:The following results show the percent inhibition of monoamine oxidase of a subject compound in comparison with the inhibitory effect of two methylamine derivatives unsubstituted on the nitrogen atom. The two derivatives were tested under the same conditions as the subject compound:
Inhibitor 1-n-propyl- 1,1-di-n-propyl- N-methyl-1,1-di-n-n-butylamin, n-butylamin, propyl-n-butylamin, hydrochlorid hydrochlorid hydrochlorid 0,01 22 1,5 3 10 0,02 25 6 1,5 0,04 35,5 11,5 3 0,06 44 11,5 0 0,08 48 14,5 0 0,10 54 14,5 3 15 Disse resultater viser, at den inhiberende virkning på monoaminoxidase er særdeles udtalt ved 1-n-propyl-n-butylamin, hydrochlorid, svag ved 1,1-di-n-propyl-n-butylamin, hydrochlorid og praktisk taget nul ved N-methyl-1,1-di-n-propyl-n-butylamin, hydrochlorid.Inhibitor 1-n-propyl-1,1-di-n-propyl-N-methyl-1,1-di-nn-butylamine, n-butylamine, propyl-n-butylamine, hydrochloride hydrochloride hydrochloride 0.01 22 1, 5 3 10 0.02 25 6 1.5 0.04 35.5 11.5 3 0.06 44 11.5 0 0.08 48 14.5 0 0.10 54 14.5 3 15 These results show, that the inhibitory effect on monoamine oxidase is highly pronounced at 1-n-propyl-n-butylamine, hydrochloride, weak at 1,1-di-n-propyl-n-butylamine, hydrochloride and practically zero at N-methyl-1, 1-di-n-propyl-n-butylamine, hydrochloride.
20 Ved den terapeutiske anvendelse af de omhandlede forbindelser administreres de normalt i form af et farmaceutisk eller veterinært præparat i en dosisenhedsform, der svarer til den anvendte administrationsform, og som indeholder en omhandlet forbindelse som virksom bestanddel sammen med en 25 farmaceutisk bærer eller ekscipient derfor. Ved oral administration kan præparatet foreligge i form af f.eks. en overtrukket eller uovertrukket tablet, en hård eller blød gelatinekapsel, en suspension eller en sirup. Præparatet kan alternativt foreligge som et suppositorie til rektal 30 administration eller en opløsning eller suspension til parenteral administration.In the therapeutic use of the compounds of the invention, they are usually administered in the form of a pharmaceutical or veterinary composition in a dosage unit form corresponding to the form of administration used, and containing a subject compound as an active ingredient together with a pharmaceutical carrier or excipient therefor. In oral administration, the composition may be in the form of e.g. a coated or uncoated tablet, a hard or soft gelatin capsule, a suspension or a syrup. Alternatively, the composition may be provided as a suppository for rectal administration or a solution or suspension for parenteral administration.
Præparatet i dosisenhedsform kan indeholde fra .5 til 50 mg, fortrinsvis fra 5 til 20 mg, af den virksomme bestanddel pr. dosisenhed ved oral administration, fra 5 til 100 mg 35 virksom bestanddel pr. dosisenhed ved rektal administration 146063 11 eller fra 1 til 20 mg virksom bestanddel pr. dosisenhed ved parenteral administration.The dosage unit form composition may contain from .5 to 50 mg, preferably from 5 to 20 mg, of the active ingredient per day. dose unit by oral administration, from 5 to 100 mg 35 active ingredient per day. dosage unit by rectal administration or from 1 to 20 mg of active ingredient per day. dose unit by parenteral administration.
De terapeutiske præparater fremstilles ved at bringe mindst én af forbindelserne med formlen I eller et farmaceutisk 5 acceptabelt syreadditionssalt deraf sammen med mindst én egnet bærer eller ekscipient deraf. Eksempler på egnede bærere eller ekscipienter er talkum, magnesiumstearat, mælkesukker, saccharose, carboxymethylcellulose, stivelser, kaolin, levilit og kakaosmør.The therapeutic compositions are prepared by bringing at least one of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof with at least one suitable carrier or excipient thereof. Examples of suitable carriers or excipients are talc, magnesium stearate, milk sugar, sucrose, carboxymethyl cellulose, starches, kaolin, levilite and cocoa butter.
10 De følgende eksempler illustrerer fremgangsmåden ifølge opfindelsen samt fremstillingen af egnede terapeutiske præparater.The following examples illustrate the method of the invention as well as the preparation of suitable therapeutic compositions.
Eksempel 1Example 1
Fremstilling af N-propargy1-1,1-di-n-propyl-n-butylamin, 15 hydrochlorid_ a) N-Propargyl-1,1-di-n-propyl-n-butylamin.Preparation of N-Propargy1-1,1-di-n-propyl-n-butylamine, hydrochloride a) N-Propargyl-1,1-di-n-propyl-n-butylamine.
En blanding af 11,9 g (0,1 mol) propargylbromid, 25 g natriumhydrogencarbonat, 250 ml ethanol og 19,7 g (0,1 mol) 1,1-di-n-propyl-n-butylamin tilbagesvales i 48 timet. Efter 20 frafiltrering af den uopløselige del og afdampning af etha-nolet behandles blandingen med en fortyndet natriumhydroxidopløsning. Den organiske fase ekstraheres med ether og destilleres under anvendelse af en søjle med roterende bånd.A mixture of 11.9 g (0.1 mole) of propargyl bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 19.7 g (0.1 mole) of 1,1-di-n-propyl-n-butylamine is refluxed for 48 hours. . After filtering off the insoluble portion and evaporation of the ethanol, the mixture is treated with a dilute sodium hydroxide solution. The organic phase is extracted with ether and distilled using a rotary band column.
På denne måde isolerer man 10 g N-propargyl-l,l-di-n-25 propyl-n-butylamin i form af en bleggul væske. Kp. 94-96°C under 5 mm Hg. Udbytte 51%.In this way, 10 g of N-propargyl-1,1-di-n-25 propyl-n-butylamine is isolated in the form of a pale yellow liquid. Kp. 94-96 ° C under 5 mm Hg. Yield 51%.
Under anvendelse af samme fremgangsmåde som beskrevet ovenfor, med med andre udgangsmaterialer, fremstilles følgende forbindelser:Using the same procedure as described above, with other starting materials, the following compounds are prepared:
30 Forbindelse Kp. °CCompound Kp. ° C
N-Methyl-1,1-di-n-propyl-n-butylamin 84 (13 mm Hg) N-Methyl-l-n-propyl-l-isobutyl-n- 86 butylamin (12 mm Hg) 12 146063 b) N-Propargyl-l,l-di-n-propyl-n-butylamin, hydrochlorid.N-Methyl-1,1-di-n-propyl-n-butylamine 84 (13 mm Hg) N-Methyl-1n-propyl-1-isobutyl-n- 86 butylamine (12 mm Hg) b) N- Propargyl-1,1-di-n-propyl-n-butylamine hydrochloride.
Ved at boble tør gasformig hydrogenchlorid gennem en ethe-risk opløsning af den opnåede amin udfældes det ønskede hydrochlorid, der derefter frafiltreres og tørres.By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine obtained, the desired hydrochloride is precipitated which is then filtered off and dried.
5 på denne måde får man N-propargyl-1,1-di-n-propyl-n-butyl-amin, hydrochlorid i form af krystaller. Smp. 154-155°C. Kvantitativt udbytte.In this way, N-propargyl-1,1-di-n-propyl-n-butylamine hydrochloride is obtained in the form of crystals. Mp. 154-155 ° C. Quantitative yield.
Efter den samme fremgangsmåde som beskrevet ovenfor, men under anvendelse af andre udgangsforbindelser, fremstilles 10 følgende forbindelser: N-Methyl-1,1-di-n-propyl-n-butylamin, hydrochlorid. Smp. 133-134°C.Following the same procedure as described above, but using other starting compounds, the following compounds are prepared: N-Methyl-1,1-di-n-propyl-n-butylamine, hydrochloride. Mp. 133-134 ° C.
N-Methyl-l-n-propyl-l-isopropyl-n-butylamin, hydrochlorid.N-Methyl-1-n-propyl-1-isopropyl-n-butylamine hydrochloride.
Smp. 144—145°C.Mp. 144-145 ° C.
15 Eksempel 2Example 2
Fremstilling af N-methyl-l-n-propyl-l-allyl-n-butylamin, fumarat_Preparation of N-methyl-1-n-propyl-1-allyl-n-butylamine, fumarate
Til en opløsning af 2,32 g (0,02 mol) fumarsyre i 400 ml acetone sættes under omrøring 3,38 g (0,02 mol) N-methyl-20 1-n-propyl-l-allyl-n-butylamin, der er fremstilllet under anvendelse af den i eksempel 1 angivne fremgangsmåde, opløst i 30 ml acetone.To a solution of 2.32 g (0.02 mol) of fumaric acid in 400 ml of acetone is added, with stirring, 3.38 g (0.02 mol) of N-methyl-20-1-n-propyl-1-allyl-n-butylamine. prepared using the procedure of Example 1, dissolved in 30 ml of acetone.
Omrøringen fortsættes i en time, hvorefter de udskilte farveløse krystaller isolerés. Krystallerne vaskes med acetone 25 og tørres.Stirring is continued for one hour, after which the separated colorless crystals are isolated. The crystals are washed with acetone 25 and dried.
På denne måde fremstilles 5,2 g N-methyl-l-n-propyl-l-allyl-n-butylamin, fumarat med smp. 149°C i et udbytte på 91%.In this way, 5.2 g of N-methyl-1-n-propyl-1-allyl-n-butylamine, fumarate with m.p. 149 ° C in a yield of 91%.
Eksempel 3.Example 3
Fremstilling af N-methy1-1-n-propyl-l-isobutyl-n-butylamin, 30 hydrochlorid.Preparation of N-methyl-1-n-propyl-1-isobutyl-n-butylamine hydrochloride.
I 150 ml absolut ethanol opløses 10,4 g N-methyl-l-n-propyl- 13 146063 1-isobutyl-n-butylamin, der er fremstillet under anvendelse af den i eksempel 1 angivne fremgangsmåde, og til den dannede opløsning sættes 5,6 ml koncentreret saltsyre, hvorpå opløsningen inddampes til tørhed.In 150 ml of absolute ethanol, dissolve 10.4 g of N-methyl-1n-propyl-1-isobutyl-n-butylamine prepared using the procedure of Example 1 and add to the resulting solution 5.6 ml of concentrated hydrochloric acid, and the solution is evaporated to dryness.
5 Den fremkomne olie optages i 50 ml hexan, og det ønskede hydro-chlorid krystalliserer ved afkøling. Hydrochloridet isoleres og omkrystalliseres fra isopropylether. På denne måde fås 7,5 g N-methyl-l-n-propyl-l-isobutyl-n-butylamin, hydrochlorid i et udbytte på 61%. Smp. 139°C.The resulting oil is taken up in 50 ml of hexane and the desired hydrochloride crystallizes on cooling. The hydrochloride is isolated and recrystallized from isopropyl ether. In this way 7.5 g of N-methyl-1-n-propyl-1-isobutyl-n-butylamine hydrochloride is obtained in a yield of 61%. Mp. 139 ° C.
10 Eksempel 4.Example 4.
Fremstilling af N,N-dipropargyl-l,l-di-n-propyl-n—butylamin, hydrochlorid a) N,N-Dipropargyl-l,l-di-n-propyl-n-butylamin.Preparation of N, N-dipropargyl-1,1-di-n-propyl-n-butylamine, hydrochloride a) N, N-Dipropargyl-1,1-di-n-propyl-n-butylamine.
Ved at fortsætte den i eksempel la) til opnåelse af N-propar-15 gyl-l,l-di-n-propyl-n-butylamin gennemførte destillation isoleres det tilsvarende Ν,Ν-dipropargylderivat.By continuing the distillation carried out in Example 1a) to obtain N-propargyl-1,1-di-n-propyl-n-butylamine, the corresponding Ν, Ν-dipropargyl derivative is isolated.
På denne måde får man 3 g N,N-dipropargyl-l,l-di-n-propyl-n-butylamin i form af en farveløs væske. Kp. 120°C under 5 mm Hg. Udbytte 13%.This gives 3 g of N, N-dipropargyl-1,1-di-n-propyl-n-butylamine in the form of a colorless liquid. Kp. 120 ° C below 5 mm Hg. Yield 13%.
20 Under anvendelse af den ovenfor beskrevne fremgangsmåde fremstilles ud fra tilsvarende udgangsmaterialer følgende forbindelse:Using the process described above, the following compound is prepared from the corresponding starting materials:
Forbindelse Kp. °CCompound Kp. ° C
N,N-Dimethyl-l-n-propyl-l-isobutyl-n- 25 butylamin 106-107 (17 mm Hg) b) N,N-Dipropargyl-l,l-di-n-propyl-n-butylamin, hydrochlorid.N, N-Dimethyl-1-n-propyl-1-isobutyl-n-butylamine 106-107 (17 mm Hg) b) N, N-Dipropargyl-1,1-di-n-propyl-n-butylamine hydrochloride.
Ved at boble tørt gasformigt hydrogenchlorid gennem en etherisk opløsning af N,N-dipropargyl-l,1-di-n-propyl-n-butylamin udfældes det ønskede hydrochlorid.By bubbling dry gaseous hydrogen chloride through an ethereal solution of N, N-dipropargyl-1,1-di-n-propyl-n-butylamine, the desired hydrochloride is precipitated.
Claims (2)
Priority Applications (3)
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| DK570881A DK146178C (en) | 1976-06-03 | 1981-12-22 | METHOD OF ANALOGUE FOR THE PREPARATION OF METHYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. |
| DK571081A DK146180C (en) | 1976-06-03 | 1981-12-22 | METHOD OF ANALOGUE FOR THE PREPARATION OF METHYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. |
| DK570981A DK146156C (en) | 1976-06-03 | 1981-12-22 | METHOD OF ANALOGUE FOR THE PREPARATION OF METHYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. |
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