DK156566B - METHOD OF ANALOGY FOR THE PREPARATION OF 3-AMINO-1-PHENOXY-2-PROPANOLE DERIVATIVES OR ACID ADDITION SALTS OR QUATERNARY AMMONIUM SALTS THEREOF - Google Patents
METHOD OF ANALOGY FOR THE PREPARATION OF 3-AMINO-1-PHENOXY-2-PROPANOLE DERIVATIVES OR ACID ADDITION SALTS OR QUATERNARY AMMONIUM SALTS THEREOF Download PDFInfo
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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Abstract
Description
DK 156566 BDK 156566 B
Den foreliggende opfindelse angâr en analogifremgangsmâde til fremstilling af hidtil ukendte 3-amino-l-phenoxy-2-propanolde-rivater, nemlig 3-a1kylami no-(2-chlor-3,5-dimethoxyphenoxy)-2-propanolerne med formlen I og salte deraf. Disse hidtil 5 ukendte derivater er nyttige ved sygdomsbehandling.The present invention relates to an analogous process for the preparation of novel 3-amino-1-phenoxy-2-propanol derivatives, namely the 3-alkylamino- (2-chloro-3,5-dimethoxyphenoxy) -2-propanol of formula I and salts thereof. These novel derivatives are useful in the treatment of disease.
Det er kendt, især fra fransk patentskrift nr. 3647M, nr. 4061M og nr. 70.13806 og det amerikanske patentskrift nr. 3.203.992, at dérivaterne tilherende fami 1ien af 3-amino-1-10 phenoxy-2-propanoler generelt har β-blokerende egenskaber. Det har imidlertid vist sig, at derivater fra nævnte familie al-drig har kunnet kommercia 1iseres som felge af en række ulem-per, især toleranceproblemer og/eller for korte varigheder af den j3-blokerende virkning.It is known, especially from French Patent Specification No. 3647M, No. 4061M and No. 70.13806, and U.S. Patent No. 3,203,992, that the derivatives of the family of 3-amino-1-10 phenoxy-2-propanols generally have β -blocking properties. However, it has been found that derivatives from said family have never been able to be commercialized as rims for a number of disadvantages, in particular tolerance problems and / or short durations of the β-blocking effect.
1515
Det har for nylig pà overraskende mâde vist sig, at 3-alkyl-amino-l-(2-chlor-3,5-dimethoxyphenoxy)-2-propanolerne f rem- stillet ifelge opfindelsen ikke udviser de ovennævnte ulemper, er mere effektive ved sygdomsbehandling end (i) l-(3,5-dime-20 thoxyphenoxy)-3-isopropylamino-2-propanol fra de ovennævnte patentskrifter nr. 3647M og nr. 4061M og (ii) l-(3,5-dimetho-xyphenoxy)-3-tertiobutylamino-2-propanol fra fransk patentskrift nr. 70.13806 og har lavere toxicitet end disse og er i det mindste lige sâ intéressante som propanolol, et sammenlig-25 neligt jS-blokerende middel, der har en anden struktur.It has recently been surprisingly found that the 3-alkylamino-1- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols of the present invention do not exhibit the above disadvantages, are more effective in disease treatment than (i) 1- (3,5-dimethoxyphenoxy) -3-isopropylamino-2-propanol from the aforementioned patents 3647M and 4061M and (ii) 1- (3,5-dimethoxy-xyphenoxy) ) -3-tertiobutylamino-2-propanol from French Patent No. 70,13806 and has a lower toxicity than these and is at least as important as propanolol, a comparable β-blocking agent having a different structure.
De hidtil ukendte 3-amino-l-phenoxy-2-propanolderivater, der fremstillet ifelge opfindelsen er valgt fra gruppen bestàende af 30 (i) 3-alkylamino-l-(2-chlor-3,5-dimethoxyphenoxy)-2-propanolerne med den almene formel 35The novel 3-amino-1-phenoxy-2-propanol derivatives prepared according to the invention are selected from the group consisting of the 30 (i) 3-alkylamino-1- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols of the general formula 35
DK 156566 BDK 156566 B
2 CI^O ,C1 // 'S-O-CH* -CH-CH» “NH-R (i) yJ oh 5 CH3° hvori R er CH(CH3)2 eller 0(0143)3, og (ii) deres syreadditionssalte og deres kvaternære ammonium-salte.2 C ^ OO, C1 // 'SO-CH * -CH-CH »»NH-R (i) yJ and 5CH CH CH wherein R is CH (CH3) 2 or O (0143) 3, and (ii) their acid addition salts and their quaternary ammonium salts.
10 I praksis er de foretrukne produkter fremstillet ifolge opfindelsen l-(2-chlor-3,5-dimethoxyphenoxy)-3-tertiobutylami no-2-propanol og additionssalte deraf, især hydrochloridet. Forseg hos dyr og mennesker har vist, at 3-tertiobutylaminoderivatet 15 og dets salte er mere virksomme end 3-isopropylaminoderivatet og dets salte.In practice, the preferred products prepared according to the invention are 1- (2-chloro-3,5-dimethoxyphenoxy) -3-tertiobutylamino-2-propanol and the addition salts thereof, in particular the hydrochloride. Studies in animals and humans have shown that the 3-tertiobutylamino derivative 15 and its salts are more effective than the 3-isopropylamino derivative and its salts.
Ved additionssalte forstâs i denne forbindelse syreadditions-salte, der er opnâet ved omsætning af en fri base med formlen 20 (I) med en uorganisk eller organisk syre og kvaternære ammoni- umsalte. Blandt de anvendelige syrer til at danne salte med baserne med formlen (I) kan især nævnes saltsyre, hydrogenbro-mid, salpetersyre, svovlsyre, myresyre, eddikesyre, propion-syre, oxalsyre, fumarsyre, maleinsyre, ravsyre, benzoesyre, 25 kanelsyre, mandelsyre, citronsyre, æblesyre, vinsyre, aspara-ginsyre, glutaminsyre, p-toluensulfonsyre og methansulfonsyre. Blandt forbindelserne, der gar det muligt at opnâ de kvaternære ammoniumsalte, kan især nævnes ICH3 og CICH3. Syreaddi-tionssaltene, især hydrochloriderne, er de foretrukne addi-30 tionssalte til terapeutisk anvendelse.In this connection, addition salts are understood to mean acid addition salts obtained by reacting a free base of formula 20 (I) with an inorganic or organic acid and quaternary ammonium salts. Among the useful acids to form salts with the bases of formula (I) are in particular hydrochloric acid, hydrogen bromide, nitric acid, sulfuric acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, benzoic acid, cinnamic acid, mandelic acid. , citric, malic, tartaric, aspartic, glutamic, p-toluenesulfonic and methanesulfonic. Among the compounds which make it possible to obtain the quaternary ammonium salts are notably ICH3 and CICH3. The acid addition salts, especially the hydrochlorides, are the preferred addition salts for therapeutic use.
De hidtil ukendte 3-amino-l-phenoxy-2-propanolderivater kan ifolge opfindelsen fremstilles ved en fremgangsmâde, der er kendt, under anvendelse af kendte reaktionsmetoder. Fremgangs-35 mâden, der anvendes if0lge opfindelsen, er ejendommelig ved, at man a) omsætter en 2-chlor-3,5-dimethoxyphenol med formlenThe novel 3-amino-1-phenoxy-2-propanol derivatives of the invention can be prepared by a process known in the art using known reaction methods. The process used in accordance with the invention is characterized by a) reacting a 2-chloro-3,5-dimethoxyphenol of the formula
DK 156566 BDK 156566 B
3 ch3o. Cl C VoH (II) 5 Cï^o' med epichlorhydrin III î nærværelse af pyridin til opnâelse af l-(2-chlor-3,5-dimethoxyphenoxy)-2,3-epoxypropan med formlen 10 <^0 ,C1 V 7-O-CH--CH-CH- (IV) W 2 v ch3o 15 og derpà b) omsætter det sâledes opnâede epoxid IV med en amin 20 NH2R (V) hvor R er iso-C3H7 eller tert-C.^g, i en lavere alkohol med 1-3 carbonatomer, fortrinsvis éthanol eller methanol, hvoref-25 ter en fremstillet fri base eventuelt overfores til et syread-ditionssalt eller et kvaternært ammoniumsalt.3 ch3o. Cl C VoH (II) 5 C10 with epichlorohydrin III in the presence of pyridine to give 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane of formula 10 <0> C1 V7 -O-CH - CH-CH- (IV) W 2 v ch3o 15 and then b) reacting the epoxide IV thus obtained with an amine 20 NH 2 R (V) where R is iso-C 3 H 7 or tert-C in a lower alcohol having 1-3 carbon atoms, preferably ethanol or methanol, whereupon a prepared free base is optionally transferred to an acid addition salt or a quaternary ammonium salt.
Den bedste fremgangsmâde, nâr det angâr trin a), er at omsætte 1 mol II med 4 til 10 mol III i 2 til 5 timer ved en tempera-30 tur i intervallet mellem 100 og 120°C, idet epichlorhydrinet III virker som oplosningsmiddel og pyridinen som katalysator, og med hensyn til trin b) at omsætte 1 mol epoxid IV med 8 til 12 mol amin V i nærværelse af éthanol ved reaktionsmediets ti Ibagesval ingstemperatur i mindst 3$ time.The best approach when it comes to step a) is to react 1 mol II with 4 to 10 mol III for 2 to 5 hours at a temperature in the range of 100 to 120 ° C, the epichlorohydrin III acting as a solvent and as the catalyst, and with respect to step b) reacting 1 mole of epoxide IV with 8 to 12 moles of amine V in the presence of ethanol at the reaction temperature at reflux for at least 3 hours.
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DK 156566BDK 156566B
Tabel I.Table I.
4 CH 0 Cl 3w4 CH 0 Cl 3w
5 C y-0-CH2-CHOH-CH2-NHR5 C y-O-CH 2 -CHOH-CH 2 -NHR
ΓΓ
CHjOCHjO
Produkt Kode nr. R Smeltepunkt 10--------------Product Code No. R Melting Point 10 --------------
Eksempel l(b) CRL 41058 tert-C.Hn 216°CExample 1 (b) CRL 41058 tert-C.Hn 216 ° C
4 y4 y
Eksempel 2(a) - tert-C4H9 85°CExample 2 (a) - tert-C 4 H 9 85 ° C
Eksempel 3(b) CRL 41045 iso-C3H7 206°CExample 3 (b) CRL 41045 iso-C 3 H 7 206 ° C
Eksempel 4(a) - iso-C3H7 97°CExample 4 (a) - iso-C 3 H 7 97 ° C
15 Noter: (a): fri base (b); hydrochlorid_ 3-alkyl ami no-1-(2-ch1 or-3,5-d imethoxyphenoxy)-2-propanolerne 20 med formlen (I) og deres additionssalte benyttes som /3-bloke-rende midler.Notes: (a): free base (b); The hydrochloride-3-alkyl amine no-1- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols 20 of formula (I) and their addition salts are used as / 3-blocking agents.
Opfindelsen illustreres nærmere af fclgende eksempler.The invention is further illustrated by the following examples.
25 Fremstillinq I.Preparation I.
Fremstilling af l-(2-chlor-3,5-dimethoxyphenoxy)-3-tertiobu-ty1 ami no-2-propanolhydrochlorid.Preparation of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-tertiobutylamino-2-propanol hydrochloride.
(Eksempel 1, kodenummer CRL 41 058).(Example 1, code number CRL 41 058).
30 1) 2-chlor-3,5-dimethoxyphenol.1) 2-Chloro-3,5-dimethoxyphenol.
En oplosning, der holdes ved en temperatur i intervallet mellem 35 og 40°C, og som bestâr af 75 g (0,487 mol) 3,5- dimethoxy-35 phénol og 400 ml CCl^,, tilfores i fraktioner i lobet af 2 1/2 time en mængde pâ 70,5 g (0,528 mol) N-chlorsuccinimid.A solution maintained at a temperature in the range of 35 to 40 ° C, consisting of 75 g (0.487 mol) of 3,5-dimethoxy-phenol and 400 ml of CCll, is added in fractions over 2 liters. / 2 hours an amount of 70.5 g (0.528 mol) of N-chlorosuccinimide.
Der opvarmes derpâ i 0,25 time ved en temperatur pâ ca. 70°C.It is then heated for 0.25 hours at a temperature of approx. 70 ° C.
Det dannede précipitât fjernes ved filtrering, og filtratet bringes til torhed under reduceret tryk. Den sâledes opnâedeThe formed precipitate is removed by filtration and the filtrate is brought to dryness under reduced pressure. It thus obtained
DK 156566 BDK 156566 B
5 rest efter inddampning relises ved destination under vakuum, hvorpâ destillatet vaskes med vand. Der opnâs 56,5 g (udbytte: 61,65%) 2-chlor-3,5-dimethoxy-phenol. F. (Kofler) = 57°C.5 residue after evaporation is released at destination under vacuum, whereupon the distillate is washed with water. 56.5 g (yield: 61.65%) of 2-chloro-3,5-dimethoxy-phenol are obtained. F. (Kofler) = 57 ° C.
_ mst 5 2 ) 1- ( 2-chlor-3,5-dimethoxyphenoxy ) - 2,3-epoxypropan.2) 1- (2-Chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane.
En oplosning af 40 g (0,212 mol) 2-chlor-3,5-dimethoxyphenol i 133 ml (1,697 mol) epichlorhydrin opvarmes til 115°C i 4 1 timer i nsrværelse af 0,25 ml pyridin. Reaktionsmediet bringes til terhed, resten optages i ethylacetat, og ethylacetatfasen vaskes successivt med natriumhydroxid og vand. Efter torring pâ vandfri natriumsulfat og afdampning af oplosningsmidlet opnâs en tyk brun olie. Denne olie renses ved krystallisering i isopropanol til opnâelse af 36,5 g (udbytte: 70,4%) 1 — (2 — . ch1or-3,5-dimethoxyphenoxy)-2,3-epoxypropan, der foreligger i form af et chokoladebrunt pulver. F^nst (Kofler) = 96°C.A solution of 40 g (0.212 mol) of 2-chloro-3,5-dimethoxyphenol in 133 ml (1.697 mol) of epichlorohydrin is heated to 115 ° C for 4 hours in the presence of 0.25 ml of pyridine. The reaction medium is brought to dryness, the residue is taken up in ethyl acetate and the ethyl acetate phase is washed successively with sodium hydroxide and water. After drying on anhydrous sodium sulfate and evaporation of the solvent, a thick brown oil is obtained. This oil is purified by crystallization in isopropanol to give 36.5 g (yield: 70.4%) of 1- (2 - chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane in the form of a chocolate brown powder. Found (Kofler) = 96 ° C.
3) CRL 41 058. .3) CRL 41 058..
2020
En oplosning af 36 g (0,147 mol) l-(2-chlor-3,5-dimethoxyphen-oxy)-2,3-epoxypropan og 107,5 g (1,472 mol) tert.-butylamin i 150 ml vandfri éthanol opvarmes under tilbagesvaling i 1 time. Reaktionsmediet bringes til terhed, og den sâledes op-25 nâede rest renses ved krystallisering i diisopropylether til opnâelse af 37 g l-(2-chlor-3,5-dimethoxyphenoxy)-3-tert.-butylamino-2-propanol, der fremstâr i form af et beigefarvet pulver. Finst (Kofler)' = 85°C.A solution of 36 g (0.147 mol) of 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane and 107.5 g (1.472 mol) of tert.-butylamine in 150 ml of anhydrous ethanol is heated under reflux for 1 hour. The reaction medium is brought to dryness and the residue thus obtained is purified by crystallization in diisopropyl ether to give 37 g of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-tert-butylamino-2-propanol in the form of a beige powder. Fine (Kofler) = 85 ° C.
3030
Den sâledes opnâede frie base behandles under tilbagesvaling i vandfri éthanol med ethanolhydrogenchlorid. Der dannes et bundfald, sorr. isoleres til opnâelse af-36,3 g (udbytte = 69,75%) CRL 41 058, der fremstâr som et let beigefarvet pulver, med en oploselighed pâ 12,5 g/1 i vand. F. . (Kofler) = 216°C.The free base thus obtained is treated under reflux in anhydrous ethanol with ethanol hydrogen chloride. A precipitate is formed, sorrow. isolated to give -36.3 g (yield = 69.75%) CRL 41 058, which appears as a light beige powder, with a solubility of 12.5 g / l in water. F. (Koffler) = 216 ° C.
35 mst35 mst
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66
Fremsti11inq II.Preparation II.
F rems t i lling af l-(2-chlor-3,5-dimethoxyphenoxy)-3-isopropyl-amino-2-propanolhydrochlorid.Form a mixture of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-isopropylamino-2-propanol hydrochloride.
5 (Eksempel 3; kodênummer CRL 41 045).5 (Example 3; code number CRL 41 045).
Ved at gâ frem som angivet i trin 3) ved fremstilling I, men idet tert.-butylamin erstattes med isopropylamin, opnâs CRL 41 045. Finst (Kôf1er) = 206°C.Proceeding as indicated in step 3) of Preparation I, but replacing tert-butylamine with isopropylamine, CRL 41 045 is obtained. Fine (Coefficient) = 206 ° C.
1010
Nedenfor er anfert nogle af de forseg, der er udfert med CRL 41 058 (produkt fra eksempel 1). I disse forseg, og medmindre andet anferes, administreres CRL 41 058, i en suspension i en vandig oplesning af gummiarabikum til koncentrationer storre 15 end eller 1i g med 3 g/1 og oplest i destilleret vand til kon-) centrationer under 3 g/1 ad intraperitoneal vej i et volumen pâ 20 ml/kg hos hanmus og 5 ml/kg hos hanrotter.Listed below are some of the claims made with CRL 41 058 (product of Example 1). In these experiments, and unless otherwise stated, CRL 41 058 is administered in a suspension in an aqueous solution of gum arabic to concentrations greater than or equal to 3 g / l and dissolved in distilled water to concentrations below 3 g / ml. 1 by intraperitoneal route in a volume of 20 ml / kg in male mice and 5 ml / kg in male rats.
Toksicitet.Toxicity.
2020
Hos hanmus ad I.P.-vej er DL-0 (sterste ikke dedelige dosis) sterre end 64 mg/kg, og DL-30 (den dosis, ved hvilken 30% af dyrene der) af sterrelsesordenen 128 mg/kg. CRL 41 058 er mindre toksisk end l-(3,5-dimethoxyphenoxy)-3-tert.-butyl-25 amino-2-propanol med en DL-50 ad I.P.-vej hos hanmus af ster-relsen 73 mg/kg.In male mice by I.P. pathway, DL-0 (highest non-dose dose) is higher than 64 mg / kg and DL-30 (the dose at which 30% of animals are) of the order of 128 mg / kg. CRL 41 058 is less toxic than 1- (3,5-dimethoxyphenoxy) -3-tert.-butyl-25-amino-2-propanol with a DL-50 by I.P. route in male mice of the size 73 mg / kg.
Almen adfærd og reaktioner.General behavior and reactions.
Grupper pâ 3 dyr observeres forud for og derpâ 15 minutter, 30 30 minutter, 1 time, 2 timer, 3 timer og 24 timer efter administration af CRL 41 058 ad I.P.vej bemsrkes det, at 1) hos mus 35 - doseringer pâ 0,5 mg/kg, 2'mg/kg og 8 mg/kg fremkalder ingen tydelige symptomer.Groups of 3 animals are observed before and then 15 minutes, 30 30 minutes, 1 hour, 2 hours, 3 hours and 24 hours after administration of CRL 41 058 by IP route, it is observed that 1) in mice 35 doses of 0, 5 mg / kg, 2'mg / kg and 8 mg / kg do not produce any obvious symptoms.
DK 156566( 7 - doseringen pâ 32 mg/kg tarer til en ufconstant sedativ virknii (hos 2 af de 3 dyr) og kortvarig (30 minutter), ânden0d (hos 2 ud af 3 dyr) i 15 til 30 minutter,og S 2) hos rotter - doseringer pâ 0,25 mg/kg, 1 mg/kg og 4 mg/kg fremkalder ingen tydelige symptomer, - doseringen pâ 16 mg/kg giver en kortvarig sedativ virkning 30 minutter og undertrykker respirationen (hos 2 ud af 3 dyr) i 30 minutter.DK 156566 (7 - the dosage of 32 mg / kg rates an unconstitutional sedative effect (in 2 of the 3 animals) and short-term (30 minutes), end (in 2 of 3 animals) for 15 to 30 minutes, and S 2 ) in rats - doses of 0.25 mg / kg, 1 mg / kg and 4 mg / kg do not produce any obvious symptoms, - the dose of 16 mg / kg gives a short sedative effect 30 minutes and suppresses respiration (in 2 out of 3 animals) for 30 minutes.
Undersogelse af de kardiovaskulære egenskaber.Investigation of the cardiovascular properties.
15 A - Bedovet hund.15 A - Stunned dog.
Tre hunde (gennemsnitsvægt: 13,6 kg), der er bedovet med nem- butal, indgives CRL 41 058 ad intraduodenal vej i successive 20 doser pâ 0,5 mg/kg, 1 mg/kg, 2,5 mg/kg, 5 mg/kg og 10 mg/kg.Three dogs (average weight: 13.6 kg) anesthetized with nembutal are administered CRL 41 058 by intraduodenal route in successive 20 doses of 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg and 10 mg / kg.
Blodtrykket mâles (det bar erindres, at 1 mm Hg svarer til 2 ca. 1,333 x 10 Pa), hjertefrekvensen, omsætningen i det fémorale blodomlob, omsætningen i det vertébrale blodomlob, rek-taltemperaturen og hudens farve og farven af galden ved ind-25 foring af et kateter i galdegangen efter ligatur af galde- blaaren.Blood pressure is measured (it is recalled that 1 mm Hg corresponds to 2 approximately 1.333 x 10 Pa), heart rate, circulation in the femoral blood circulation, circulation in the vertical blood circulation, rectal temperature and skin color, and color of the bile at 25 lining of a catheter in the bile duct following ligature of the gallbladder.
CRL 41 058 virker som et bradycardimiddel fra en dosis pâ 0,5 mg/kg uden nogen tydelig virkning pâ blodtrykket. Det er ikke vertebralt karudvidende. Forogelsen af den fémorale 30 omsætning er kun til stede hos en ud af tre hunde, hvor refe-renceomsaetningen er svag (24 ml/min.). Hos de to andre hunde mindskes omsætningen. Rektal- og kutantemperaturerne varierer liât. Hudfarven og galdens farve er ikke ændret.CRL 41 058 acts as a bradycardia agent from a dose of 0.5 mg / kg without any apparent effect on blood pressure. It is not a vertebral vasodilator. The enhancement of femoral 30 turnover is present only in one in three dogs where the reference turnover is weak (24 ml / min). In the other two dogs, turnover decreases. The rectal and cutaneous temperatures vary slightly. The color of the skin and the color of the bile have not changed.
35 Virkningen af isoprenalin, der er afprevet efter den samlede dosis pâ 19 mg/kg CRL 41 058, er stærkt formindsket: 3 pg/kg isoprenalin bringer det diastolske blodtryik op til 119 mm Hg i stedet for 48 mm Hg og hjertefrekvensen til 110 slag/min. i35 The effect of isoprenaline tested after the total dose of 19 mg / kg CRL 41 058 is greatly diminished: 3 pg / kg isoprenaline brings the diastolic blood pressure up to 119 mm Hg instead of 48 mm Hg and the heart rate to 110 beats /mine. in
DK 156566BDK 156566B
s stedet for 245 slag/min. hos kontroldyret. Hos to hunde, hvor isoprenalindosen er foroget til 100 Mg/kg, er tachycardivirkn-ingen ved denne dosis lavere end tachycardivi rkningen af 0,3 Mg/kg isoprenalin som kontrol.s place for 245 beats / min. with the control animal. In two dogs where the isoprenaline dose is increased to 100 Mg / kg, the tachycardia effect at this dose is lower than the tachycardivation of 0.3 Mg / kg isoprenaline as a control.
55
Hypertension ved noradrenalin er ogsâ formindsket: Ved en dosis pâ 1 jig/kg noradrenalin overstiger det systoliske blodtryk 221 mm Hg i stedet for 280 mm Hg i kontrollen.Hypertension with norepinephrine is also reduced: At a dose of 1 µg / kg norepinephrine, the systolic blood pressure exceeds 221 mm Hg instead of 280 mm Hg in the control.
10 B - Isoleret hjertekammer fra forsogskaniner.10 B - Isolated heart chamber from test rabbits.
Fem hojre hjertekamre fra fors0gskaniner anvendes for at be-stemme ρΑ^ af CRL 41 058 over for isoprenalins chronotrope effekt, efter 15 minutters kontak't er gennemsnittet af pA£ 15 8,21 + 0,272.Five right heart chambers from test rabbits are used to determine the ρΑΑ of CRL 41,058 against the chronotropic effect of isoprenaline, after 15 minutes of contact the mean of pA is £ 8.21 + 0.272.
Pâ disse hjertekamre vurderes ogsâ den rene inotrope og chronotrope virkning af CRL 41 058. Det har ikke været muligt at opnâ en gennemsnitsværdi, idet koncentrationerne og administra-20 tionsrækkefolgen af koncentrationerne er variable. CRL 41 058 har en ino+ og chrono+ virkning,der er maksimal ved den forst __8 anvendte koncentration, ligegyldigt hvilken (3 x 10 til -fi -6 10 M). Hvis koncentrationen pâ 10 M f.eks. derimod admini streras efter lavere koncentrationer, der har været stimule- 25 rende, er denne koncentration pâ 10 ^ ino og chrono (dette fænomen kunne fore til den antagelse, at der frigores cate-cholaminer).In these cardiac chambers, the pure inotropic and chronotropic effect of CRL 41 058. is also evaluated, and it has not been possible to obtain an average value, since the concentrations and the order of administration of the concentrations are variable. CRL 41 058 has an ino + and chrono + effect that is maximal at the first __8 concentration, no matter which (3 x 10 to -f -6 10 M). For example, if the concentration of 10 M on the other hand, administered at lower concentrations that have been stimulating, this concentration is 10 ^ ino and chrono (this phenomenon could lead to the assumption that cate-cholamines are released).
C - Bedovet rotte.C - Anesthetized rat.
3030
Rotter af normotendusarten bedoves med pentobarbital (75 mg/kg I.P.) og atropincres (1 mg/kg I.P.). Man mâler blodtrykket ved halspulsâren, hjertefrekvensen ved integrering af blodtrykket. Der anbringes et kateter i en halsâre til injektioner-35 ne. Hvis det er nodvendigt, opretholdes bedovelsen ved subkutan injektion af pentobarbital.Rats of the normotendus species are anesthetized with pentobarbital (75 mg / kg I.P.) and atropincres (1 mg / kg I.P.). Blood pressure is measured at the carotid artery, heart rate when integrating blood pressure. A catheter is inserted into a carotid artery for injections. If necessary, anesthesia is maintained by subcutaneous injection of pentobarbital.
99
DK 156566 EDK 156566 E
1) Bestemmelse af den virksomme g-blokerende dosis.1) Determination of the effective g-blocking dose.
Tre rotter indgives CRL 41 058 ad intraven0s vej i successive doser pâ 0,3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg og eventuelt 5 30 mg/kg. Den dosis, der blokerer tachycardien, der er ind-fort med 0,03 til 0,3 μg/kg I.V. isoprenalin (den nodvendige dosis til opnàelse af en foragelse af hjertefrekvensen fra 30 til 50 slag/min.). Det viser sig, at den dosis, det drejer sig om, er pâ 1 mg/kg I.V..Three rats are administered CRL 41 058 by intravenous route in successive doses of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg and optionally 5 30 mg / kg. The dose that blocks tachycardia injected with 0.03 to 0.3 µg / kg I.V. isoprenaline (the dose needed to achieve a decrease in heart rate from 30 to 50 beats / min). It turns out that the dose at issue is 1 mg / kg I.V.
10 2 ) Varighed af /3-blokeringsvirkninqen.2) Duration of the / 3 blocking effect.
Fem rotter indgives 1 mg/kg CRL 41 058 ad I.V.-vej. Man be- mærker, at: 15 - det diastoliske blodtryk ikke ændres, det forbliver omkring 91 mm Hg, og - hjertefrekvensen ændres i lobet af 5 minutter fra 345 tilFive rats are administered 1 mg / kg CRL 41 058 by I.V. route. It is noted that: - 15 - the diastolic blood pressure does not change, it remains about 91 mm Hg, and - the heart rate changes in 5 minutes from 345 to
O QO Q
290 slag/min. (dvs. -16%), det maksimale bradycardi opnâs efter 20 minutter:280 slag/min. (dvs. -19%). Efter 90 minutter er hjertefrekvensen 307 slag/min. (dvs. -11%).290 bpm (ie -16%), the maximum bradycardia is reached after 20 minutes: 280 beats / min. (i.e. -19%). After 90 minutes, the heart rate is 307 beats / min. (i.e., -11%).
Pâ den anden side sndrer en dosis pâ 0,03 |ig/kg I.V. af iso-2g prenalins - blodtrykket fra 91 til 65 mm Hg (dvs. -26 mm Hg). Efter 1 (mg/kg I.V. CRL 41 058 er forskellen i blodtryk +8 ram Hg (-69% i forhold til ændringen i kontrollen) fra 5 minutter 30 og i lobet af de 2 timers observation, og - hjertefrekvensen fra 345 til 384 slag/min. (dvs. +39 slag/ min.). Tachycardien er fuldstændig inhiberet af CRL 41 058 efter 5 minutter, genoptager 50% af sin værdi efter 20 minut- 3g ter. Den er oppe pâ 92% af sin værdi efter 60 minutter.On the other hand, a dose of 0.03 µg / kg I.V. of iso-2g prenalins - blood pressure from 91 to 65 mm Hg (ie -26 mm Hg). After 1 (mg / kg IV CRL 41 058, the difference in blood pressure is +8 ram Hg (-69% relative to the change in control) from 5 minutes 30 and during the 2 hour observation, and - heart rate from 345 to 384 beats The tachycardia is completely inhibited by CRL 41 058 after 5 minutes, resumes 50% of its value after 20 minutes, and is up to 92% of its value after 60 minutes. minutes.
Endelig observeres hos 5 kontrolrotter, der modtager fysiolo-gisk sérum i stedet for produktet, at:Finally, in 5 control rats receiving physiological semen instead of the product, it is observed that:
DK 156566 BDK 156566 B
10 -arterietrykket forbliver konstant; hypotension ved isoprena-linet aftager roed 40% i lebet af forsoget, og - hjertefrekvensen aftager med 28 slag/min. som folge af nem-5 butalinjektioner, der er n0dvendige til vedligeholdelse af bedevelsen. Tachycardi ved isoprenalinet forbliver konstant i lobet af de 2 timers observation.The 10 arterial pressure remains constant; hypotension in the isoprenaline line decreases red 40% in the course of the trial, and - the heart rate decreases by 28 beats / min. as a result of easy-5 butal injections necessary to maintain the anesthesia. Tachycardia at the isoprenaline remains constant over the course of the 2 hours of observation.
D - Vâgen rotte.D - The walls rot.
1010
Seks rotter med genetisk forârsaget forhojet blodtryk iaed et kateter, der er indfort i den fémorale blodâre, indgives CRL 41 058 i en dosis pâ 20 rng/kg V.B..Six rats with genetically caused elevated blood pressure in a catheter inserted into the femoral vein are administered CRL 41 058 at a dose of 20 rng / kg V.B.
Blodtrykket sndres fra 191 til 167 mm Hg efter 6 timer (-13%, statistisk signifikant sndring). Hjertefrekvensen aftager efter 5 minutter og sndres fra 382 til 322 slag/min.·. (-15%, statistisk signifikant ændring). Den maksimale bradycardi nâs efter 2 timer (305 slag/min, dvs. -20%, statistisk sig-2Q nifikant sndring), den aftager derpâ til efter 7 timer at være 322 slag/min., (dvs. -15%, statistisk signifikant ændring).Blood pressure changes from 191 to 167 mm Hg after 6 hours (-13%, statistically significant change). Heart rate decreases after 5 minutes and changes from 382 to 322 beats / min. (-15%, statistically significant change). The maximum bradycardia is reached after 2 hours (305 beats / min, i.e. -20%, statistically significant 2Q significant change), it decreases to be 322 beats / min after 7 hours (i.e. -15%, statistically significant change).
24 timer efter administration af CRL 41 058 ses det, at blodtrykket igen har nâet sin kontrolværdi, medens hjertefrekven-25 sen endnu er 330 slag/min. (dvs. -13%, statistisk signifikant ændring).Twenty-four hours after administration of CRL 41 058, it is seen that blood pressure has again reached its control value, while the heart rate is still 330 beats / min. (i.e. -13%, statistically significant change).
E - Konklusion.E - Conclusion.
Det folger af de ovennævnte forsog, at CRL 41 058 er et meget godt β-blokerende middel.It follows from the above attempts that CRL 41 058 is a very good β-blocking agent.
De kliniske forseg har hos mennesket bekræftet betydningen af den j3-blokerende virkning af CRL 41 058 ved en daglig dosis 35 pâ 40 til 50 mg (fordelt pâ 2 til 3 indtag) i 2 til 6 uger.The clinical trials in humans have confirmed the importance of the β-blocking effect of CRL 41 058 at a daily dose of 35 of 40 to 50 mg (distributed over 2 to 3 intakes) for 2 to 6 weeks.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8217934A FR2534908A1 (en) | 1982-10-26 | 1982-10-26 | NOVEL 3-AMINO-1-PHENOXY-2-PROPANOL DERIVATIVES, THERAPEUTIC USE AND PREPARATION METHOD |
| FR8217934 | 1982-10-26 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK490983D0 DK490983D0 (en) | 1983-10-26 |
| DK490983A DK490983A (en) | 1984-04-27 |
| DK156566B true DK156566B (en) | 1989-09-11 |
| DK156566C DK156566C (en) | 1990-02-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK490983A DK156566C (en) | 1982-10-26 | 1983-10-26 | METHOD OF ANALOGY FOR THE PREPARATION OF 3-AMINO-1-PHENOXY-2-PROPANOLE DERIVATIVES OR ACID ADDITION SALTS OR QUATERNARY AMMONIUM SALTS THEREOF |
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| Country | Link |
|---|---|
| EP (1) | EP0110746B1 (en) |
| JP (1) | JPS5995244A (en) |
| AT (1) | ATE20339T1 (en) |
| AU (1) | AU565183B2 (en) |
| CA (1) | CA1227220A (en) |
| CS (1) | CS235985B2 (en) |
| DE (1) | DE3364087D1 (en) |
| DK (1) | DK156566C (en) |
| ES (1) | ES8406062A1 (en) |
| FI (1) | FI78903C (en) |
| FR (1) | FR2534908A1 (en) |
| GR (1) | GR77581B (en) |
| HU (1) | HU188975B (en) |
| IE (1) | IE56128B1 (en) |
| IL (1) | IL70061A0 (en) |
| MA (1) | MA19937A1 (en) |
| MX (1) | MX155997A (en) |
| NZ (1) | NZ206050A (en) |
| OA (1) | OA07575A (en) |
| SU (1) | SU1223841A3 (en) |
| ZA (1) | ZA837922B (en) |
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1983
- 1983-10-21 CA CA000439481A patent/CA1227220A/en not_active Expired
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- 1983-10-24 IE IE2487/83A patent/IE56128B1/en not_active IP Right Cessation
- 1983-10-25 NZ NZ206050A patent/NZ206050A/en unknown
- 1983-10-25 DE DE8383402068T patent/DE3364087D1/en not_active Expired
- 1983-10-25 SU SU833657054A patent/SU1223841A3/en active
- 1983-10-25 MX MX199210A patent/MX155997A/en unknown
- 1983-10-25 AU AU20566/83A patent/AU565183B2/en not_active Ceased
- 1983-10-25 ES ES526737A patent/ES8406062A1/en not_active Expired
- 1983-10-25 EP EP83402068A patent/EP0110746B1/en not_active Expired
- 1983-10-25 AT AT83402068T patent/ATE20339T1/en not_active IP Right Cessation
- 1983-10-25 GR GR72781A patent/GR77581B/el unknown
- 1983-10-25 ZA ZA837922A patent/ZA837922B/en unknown
- 1983-10-26 DK DK490983A patent/DK156566C/en not_active IP Right Cessation
- 1983-10-26 OA OA58146A patent/OA07575A/en unknown
- 1983-10-26 JP JP58199309A patent/JPS5995244A/en active Pending
- 1983-10-26 HU HU833674A patent/HU188975B/en not_active IP Right Cessation
- 1983-10-26 IL IL70061A patent/IL70061A0/en unknown
- 1983-10-26 FI FI833921A patent/FI78903C/en not_active IP Right Cessation
- 1983-10-26 CS CS837863A patent/CS235985B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA1227220A (en) | 1987-09-22 |
| FR2534908B1 (en) | 1985-03-08 |
| NZ206050A (en) | 1987-04-30 |
| FI78903B (en) | 1989-06-30 |
| IE56128B1 (en) | 1991-04-24 |
| MX155997A (en) | 1988-06-13 |
| ATE20339T1 (en) | 1986-06-15 |
| EP0110746B1 (en) | 1986-06-11 |
| IL70061A0 (en) | 1984-01-31 |
| DK156566C (en) | 1990-02-12 |
| DE3364087D1 (en) | 1986-07-17 |
| ES526737A0 (en) | 1984-07-01 |
| GR77581B (en) | 1984-09-24 |
| ZA837922B (en) | 1984-06-27 |
| IE832487L (en) | 1984-04-26 |
| HU188975B (en) | 1986-05-28 |
| ES8406062A1 (en) | 1984-07-01 |
| FI78903C (en) | 1989-10-10 |
| JPS5995244A (en) | 1984-06-01 |
| EP0110746A1 (en) | 1984-06-13 |
| DK490983A (en) | 1984-04-27 |
| SU1223841A3 (en) | 1986-04-07 |
| FI833921A (en) | 1984-04-27 |
| CS235985B2 (en) | 1985-05-15 |
| AU565183B2 (en) | 1987-09-10 |
| FR2534908A1 (en) | 1984-04-27 |
| DK490983D0 (en) | 1983-10-26 |
| AU2056683A (en) | 1984-05-03 |
| MA19937A1 (en) | 1984-07-01 |
| FI833921A0 (en) | 1983-10-26 |
| OA07575A (en) | 1985-03-31 |
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