NO130943B

NO130943B -

Info

Publication number: NO130943B
Application number: NO43271A
Authority: NO
Inventors: A Foldes; G Delmar
Original assignee: Delmar Chem
Priority date: 1970-02-06
Filing date: 1971-02-05
Publication date: 1974-12-02
Also published as: NO130943C; DE2105418A1; JPS5118484B1; DE2105418B2; FR2081494A1; CH540214A; CA957373A; FR2081494B1; DE2105418C3; SE375756B; GB1336632A

Description

Analogifremgangsmåte ved fremstilling av terapeutisk aktive aminsalter av p-klorfenoxyisosmørsyre. Analogous method in the preparation of therapeutically active amine salts of p-chlorophenoxyisobutyric acid.

Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktive aminsalter av p-klorfenoxyiso-smørsyre. The present invention relates to an analogous method for the production of therapeutically active amine salts of p-chlorophenoxyisobutyric acid.

p-klorfenoxyisosmørsyre som har formelen: p-chlorophenoxyisobutyric acid having the formula:

og alka limet all - og jordalkalimetallsalter derav, såvel som estere som ethyl-Zf-klor-2-fenoxyisobutyrat (vanlig betegnet som "Clofibrate"), er kjent for å redusere konsentrasjonen av kolesterol i and alka limet all - and alkaline earth metal salts thereof, as well as esters such as ethyl-Zf-chloro-2-phenoxyisobutyrate (commonly referred to as "Clofibrate"), are known to reduce the concentration of cholesterol in

blodserum. Av denne grunn har noen av disse forbindelser, særlig "Clofibrate" selv, vært anvendt ved behandling av slike tilstander som hjertekarsykdommer og artherosclerose. Slike forbindelser, som den best kjente for øyeblikket, "Clofibrate", fåes imidlertid vanligvis i form av oljer, eksempelvis er "Clofibrate" en farveløs til blekt gul olje med et kokepunkt på l48-150°C/20 mm, methyl-4-klor-2-fenoxyisobutyrat er en olje med kokepunkt l48-l50°C/20 mm, n-propyl-4-klor-2-fenoxyisobutyrat er en olje med kokepunkt på 167-l69°C/15 mm, og n-butyl-4-klor-2-fenoxyisobutyrat er en olje med kokepunkt 178_182°C/15 mm. Disse forbindelser er følgelig ubekvemme å håndtere og må i alminnelighet administreres oralt i form av emul-sjoner eller kapsler. Denne orale administrasjon av slike forbindelser er ikke bare mindre bekvem enn administrasjon av et fast pre-parat som tabletter, men det har også vist seg å være forbundet med gastro-intestinale forstyrrelser som diarrhoea eller irritasjon av slimhinnen i fordøyelseskanalen. blood serum. For this reason, some of these compounds, especially "Clofibrate" itself, have been used in the treatment of such conditions as cardiovascular disease and atherosclerosis. However, such compounds, such as the best known at present, "Clofibrate", are usually obtained in the form of oils, for example, "Clofibrate" is a colorless to pale yellow oil with a boiling point of l48-150°C/20 mm, methyl-4- chloro-2-phenoxyisobutyrate is an oil with a boiling point of 148-150°C/20 mm, n-propyl-4-chloro-2-phenoxyisobutyrate is an oil with a boiling point of 167-169°C/15 mm, and n-butyl- 4-chloro-2-phenoxyisobutyrate is an oil with a boiling point of 178-182°C/15 mm. These compounds are consequently inconvenient to handle and must generally be administered orally in the form of emulsions or capsules. This oral administration of such compounds is not only less convenient than administration of a solid preparation such as tablets, but it has also been shown to be associated with gastro-intestinal disturbances such as diarrhea or irritation of the mucosa of the digestive tract.

Det er også kjent at visse tertiære monoaminsalter av p-klor-fenoxyisosmørsyre oppviser aktivitet i forbindelse med reduksjon av blodserumkolesterolspeil. Dimethylaminoethanol- og diisopropylamin-saltene er spesielt omtalt i Boll. Chem. Pharm. 108, 292 (I969) og Chem. Abs. 7_2_, 11204 g (1970). It is also known that certain tertiary monoamine salts of p-chloro-phenoxyisobutyric acid exhibit activity in connection with the reduction of blood serum cholesterol levels. The dimethylaminoethanol and diisopropylamine salts are particularly discussed in Boll. Chem. Pharm. 108, 292 (1969) and Chem. Abs. 7_2_, 11204 g (1970).

I sammenligningsforsøk mellom det nye ethylendiaminsalt som fremstilles ifølge oppfinnelsen, og ethylesteren og dimethylamino-ethanolsaltet av p-klorfenoxyisosmørsyre, har det vært vist at effektiviteten av det nye diaminsalt er parallell med effektiviteten av det standarde og best kjente terapeutiske middel, ethylesteren (dvs. "Clofibrate"), og betraktelig overstiger effektiviteten av det tertiære monoaminsalt, med hensyn til serumkolesterolreduksjon. Dess-uten er det nye diaminsalt som fremstilles ifølge oppfinnelsen, mere virksomt enn både "Clofibrate" eller det tertiære monoaminsalt med hensyn til reduksjon av serumtriglycerid. In comparison experiments between the new ethylenediamine salt produced according to the invention, and the ethyl ester and the dimethylaminoethanol salt of p-chlorophenoxyisobutyric acid, it has been shown that the effectiveness of the new diamine salt is parallel to the effectiveness of the standard and best known therapeutic agent, the ethyl ester (i.e. " Clofibrate"), and considerably exceeds the effectiveness of the tertiary monoamine salt, with regard to serum cholesterol reduction. In addition, the new diamine salt produced according to the invention is more effective than both "Clofibrate" or the tertiary monoamine salt with regard to reducing serum triglyceride.

Et mål ved foreliggende oppfinnelse er å fremskaffe organiske salter av ovennevnte p-klorfenoxyisosmørsyre som vanligvis fåes i form av krystallinsk pulver, og som følgelig er mere bekvemme å håndtere og har andre betydningsfulle fordeler sammenlignet med de flytende (oljeaktige) derivater som tidligere er kjent. Det har nu vist seg at en spesiell ny gruppe av laverealkylendiaminsalter av ovennevnte p-klorfenoxyisosmørsyre vanligvis erholdes i krystallinsk pulverform som lett kan håndteres og bearbeides til faste farmasøy-tiske preparater som tabletter, som er mere bekvemt administrerbare enn de flytende preparater som tidligere er kjent, med nedsatte bi-virkninger . An aim of the present invention is to provide organic salts of the above-mentioned p-chlorophenoxyisobutyric acid which are usually obtained in the form of crystalline powder, and which are consequently more convenient to handle and have other significant advantages compared to the liquid (oily) derivatives previously known. It has now been shown that a special new group of lower alkylenediamine salts of the above-mentioned p-chlorophenoxyisobutyric acid is usually obtained in crystalline powder form which can be easily handled and processed into solid pharmaceutical preparations such as tablets, which are more conveniently administered than the liquid preparations previously known , with reduced side effects.

Foreliggende oppfinnelse angår således en fremgangsmåte ved fremstilling av nye forbindelser som er terapeutisk aktive aminsalter av p-klorfenoxyisosmørsyre med den generelle formel: hvor x er lavere alkylen. Ifølge oppfinnelsen fremstille? disse salter med formel I ved at 1 molekvivalent av p-klorfenoxyisosmørsyre omsettes med 0,5 molekvivalent av et diamin med den generelle formel: The present invention thus relates to a method for the production of new compounds which are therapeutically active amine salts of p-chlorophenoxyisobutyric acid with the general formula: where x is lower alkylene. According to the invention produced? these salts with formula I by reacting 1 mol equivalent of p-chlorophenoxyisobutyric acid with 0.5 mol equivalent of a diamine with the general formula:

hvor X er som ovenfor angitt, og det således dannede salt utvinne-', fra reaksjonsmediet. where X is as indicated above, and the salt thus formed is extracted from the reaction medium.

Det foretrukne diaminsalt med formel I er ethylendiaminsaIt et. The preferred diamine salt of formula I is the ethylenediamine salt.

Ved utførelse av foreliggende fremgangsmåte ved fremstilling When carrying out the present method during manufacture

av aminsaltene omsettes det passende amin og den frie p-klorf <-noxy-isosmørsyre med hverandre i et passende oppiøsningsmidde1. Oppløs - ningsmidlet er bekvemt en ikke-po la r organisk væske hvori begge reak-tantene er lett oppløselige. Det organiske oppløsningsmidde1 ^om foretrekkes, er benzen, men andre passende oppløsningsmidler for reaksjonen innbefatter kloroform, toluen og diethy1et her. of the amine salts, the appropriate amine and the free p-chlorophenoxy-isobutyric acid are reacted with each other in a suitable solvent1. The solvent is conveniently a non-polar organic liquid in which both reactants are easily soluble. The preferred organic solvent is benzene, but other suitable solvents for the reaction include chloroform, toluene and diethyl ether herein.

Reaksjonen utføres fortrinnsvis under værelsetemperatur. og om-rådet lO-1.5°C gir vanligvis den glatte reaksjon og høyeste utbytter av de ønskede aminsalter. Reaksjonen kan imidlertid utføres ved noe lavere og høyere temperatur, skjønt temperaturer over værelsetempara-tur er tilbøyeligetil å begunstige gummidannelse og senke utbyttene, så de bør fortrinnsvis unngåes. The reaction is preferably carried out at room temperature. and the range 10-1.5°C usually gives the smoothest reaction and highest yields of the desired amine salts. The reaction can, however, be carried out at somewhat lower and higher temperatures, although temperatures above room temperature tend to favor gum formation and lower yields, so they should preferably be avoided.

De således erholdte aminsalter faller typisk ut av reaksjonsmediet. De fraskilles på konvensjonelt vis, f.eks. ven filtrering, og om nødvendig omkrystalliseres de fra et organisk opplo-ningsmiddel for å få i det vesentlige rent aminsalt , typisk, i form av et fint, krystallinsk pulver. The amine salts thus obtained typically fall out of the reaction medium. They are separated in the conventional way, e.g. by filtration, and if necessary they are recrystallized from an organic solvent to obtain essentially pure amine salt, typically in the form of a fine, crystalline powder.

Toksikologisk e pr øver Toxicological tests

Den akutte orale toksisitet av den kjente forbindelse, ethyl-4-klor-2-fenoxyisobutyrat ("Clofibrate") og det nye ethylendiaminsalt av p-klorfenoxyisosmørsyre ble bestemt både i mus og rotter. The acute oral toxicity of the known compound, ethyl-4-chloro-2-phenoxyisobutyrate ("Clofibrate") and the new ethylenediamine salt of p-chlorophenoxyisobutyric acid was determined in both mice and rats.

Metode Method

Albino-mus som veiet 18 - 20 g og albino-rott er som veiet Albino mice weighed 18 - 20 g and albino rats weighed the same

150 - 200 g erholdt fra the Canadian Breeding Laboratories, ble anvendt. Får ("Purina Rat Chow") ble ikke gitt i 4 timer før droge-behandlingen, men ble, med vann ad libitum gitt efterpå. Efter om-rådebestemmende studier i begge arter ble en fullstendig akutt toksi-sitetsundersøkelse utført under anvendelse av ti dyr pr. dosenivå, likelig fordelt med hensyn til kjønn. Begge forbindelser ble ad-ministrert til begge arter oralt på en mg/kg legemsvektsbasis. Tegn på akutt forgiftning såvel som død i løpet av 24 timer eiter droge-administrering ble opptegnet. Alle overlevende dyr ble beholdt i de følgende 14 dager for å påvise forsinket dødelighet. Alle samlede dødelighetsdata ble analysert statistisk i henhold til metoden til Litchfield and Wilcoxon (J. Pharmacol. Exper. Therap. 9.6, 99 - H3> 1949). 150 - 200 g obtained from the Canadian Breeding Laboratories was used. Sheep ("Purina Rat Chow") were not given for 4 hours before the drug treatment, but were, with water ad libitum, given afterwards. After area-determining studies in both species, a complete acute toxicity study was carried out using ten animals per dose level, equally distributed with regard to gender. Both compounds were administered to both species orally on a mg/kg body weight basis. Signs of acute poisoning as well as death within 24 hours of drug administration were recorded. All surviving animals were kept for the following 14 days to detect delayed mortality. All pooled mortality data were analyzed statistically according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exper. Therap. 9.6, 99 - H3> 1949).

R esultater R esults

En dataanalyse som oppsummerer resultatene av de akutte toksi-kologiske prøver for begge forbindelser i mus og rotter, er angitt i tabell i. A data analysis summarizing the results of the acute toxicological tests for both compounds in mice and rats is given in Table i.

Samrn endra g , Samrn endra g ,

Fra data angitt i ovenstående tabell kan det sees at i mus ble det ikke funnet at den ene forbindelse var mer eller mindre giftig enn den annen, med LD^Q-verdier på 1570 <+> 171,7 mg/kg for "Clofibrate" og 1700 t 243,5 for ethylendiaminsaIt et. Et lignende resultat ble funnet i rotter, hvor de respektive LD^Q-verdier var 1900 t 313.1 mg/kg for "Clofibrate" og 1850 t 148,5 mg/kg for ethy.lendiaminsaltet . From the data given in the above table, it can be seen that in mice, one compound was not found to be more or less toxic than the other, with LD^Q values of 1570 <+> 171.7 mg/kg for "Clofibrate" and 1700 h 243.5 for ethylenediamine salt et. A similar result was found in rats, where the respective LD^Q values were 1900 h 313.1 mg/kg for "Clofibrate" and 1850 h 148.5 mg/kg for the ethylenediamine salt.

Oppfinnelsen vil bli illustrert nærmere ved de etterfølgende eksempler. The invention will be illustrated in more detail by the following examples.

Eksempel 1 Example 1

E thylendiaminsalt E thylenediamine salt

1 g (0,0166 mol) ethylendiamin i 5 ml tørr benzen ble tilsatt til en omrørt oppløsning inneholdende 7,1 g (0,033 mol) p-klorfenoxy-isosmørsyre i 135 ml tørr benzen i en Erlenmeyerkolbe. Blandingen ble avkjølt i et isbad til ca. 10°C, og en temperatur på 10 - 15°C ble opprettholdt i 2 timer, hvorunder blandingen ble stadig omrørt. Ethylendiaminsaltet av p-klorfenoxyisosmørsyre som feltes, ble i ra - filtrert, vasket med tørr benzen og tørret ved 50°C i vakuum-ekssikator. Dette materiale ble omkrystallisert fra methanol/ether, hvilket ga 6,8 g av det ønskede ovennevnte produkt, smeltepunkt 187 - 192°C, utbytte 82,9%. Dette produkt var i form av et hvitt , nesten lukt løst, krystallinsk pulver. 1 g (0.0166 mol) of ethylenediamine in 5 ml of dry benzene was added to a stirred solution containing 7.1 g (0.033 mol) of p-chlorophenoxy-isobutyric acid in 135 ml of dry benzene in an Erlenmeyer flask. The mixture was cooled in an ice bath to approx. 10°C, and a temperature of 10-15°C was maintained for 2 hours, during which the mixture was constantly stirred. The ethylenediamine salt of p-chlorophenoxyisobutyric acid which precipitates was filtered off, washed with dry benzene and dried at 50°C in a vacuum desiccator. This material was recrystallized from methanol/ether to give 6.8 g of the desired above product, mp 187-192°C, yield 82.9%. This product was in the form of a white, almost odorless, crystalline powder.

A na lyse A na light

Beregnet for C22<H>3cF 2°6C12: C 53,99%; H 6,17%; N 5,72% Calculated for C22<H>3cF 2°6C12: C 53.99%; H 6.17%; N 5.72%

Funnet: C 54,14%; H 6,05%; N 5,64%. Found: C 54.14%; H 6.05%; N 5.64%.

Infrarødt spek trum Infrared spectrum

Det infrarøde spektrum av denne forbindelse tott i en Nujol - pasta er gjengitt som fig. IA og B i de vedlagte tegninger. The infrared spectrum of this compound in a Nujol paste is reproduced as fig. IA and B in the attached drawings.

Eksempe 1 2_ Example 1 2_

Hexameth ylendiamin salt Hexameth ylenediamine salt

1 g (0.008 mol) hexamethylendiamin ble tilsatt til en omrørt oppløsning inneholdende 3,64 g (0,016 mol) p-klorfenoxyisosmørsyre i 1 g (0.008 mol) hexamethylenediamine was added to a stirred solution containing 3.64 g (0.016 mol) p-chlorophenoxyisobutyric acid in

70 ml tørr benzen i en Er1enmeyerkolbe. Blandingen ble avkjølt i 70 ml of dry benzene in an Er1enmeyer flask. The mixture was cooled in

et isbad til ca. 10°C,og en temperatur på lo - 15°C ble opprettholdt i 2 timer hvorunder blandingen ble omrørt kontinuerlig. Tetra-methylendiaminsaltet av p-klorfenoxyisosmørsyre som feltes, ble fra- an ice bath for approx. 10°C, and a temperature of 0 - 15°C was maintained for 2 hours during which the mixture was stirred continuously. The tetra-methylenediamine salt of p-chlorophenoxyisobutyric acid which precipitates was de-

filtrert, vasket med tørr benzen og tørret ved 50°C i vakuumekssika-tor. Dette materiale ble omkrystallisert fra methylaIkohol, hvilket g3 4)0 g av det ønskede ovennevnte produkt, smeltepunkt 221 - 223°C, utbytte 86,2%. Dette produkt var i form av et hvitt, nesten lukt-fritt, krystallinsk pulver. filtered, washed with dry benzene and dried at 50°C in a vacuum desiccator. This material was recrystallized from methyl alcohol, which gave 40 g of the desired above product, mp 221-223°C, yield 86.2%. This product was in the form of a white, almost odorless, crystalline powder.

Analyse Analysis

Beregnet for C26H38N2°6C12: C 57,27%; H 7,07%; N 5,13%. Calculated for C26H38N2°6C12: C 57.27%; H 7.07%; N 5.13%.

Funnet: C 57,l4%; H 6,87%; N 5,27%. Found: C 57.14%; H 6.87%; N 5.27%.

Infrarødt spektrum Infrared spectrum

Det infrarøde spektrum av denne forbindelse tatt i en Nujol-pasta, er angitt som fig. 2A og B i de vedlagte tegninger. The infrared spectrum of this compound taken in a Nujol paste is given as fig. 2A and B in the attached drawings.

1. Analogifremgangsmåte ved fremstilling av terapteutisk aktive aminsalter av p-klorfenoxyisosmørsyre med den generelle formel: 1. Analogous method for the production of therapeutically active amine salts of p-chlorophenoxyisobutyric acid with the general formula:

hvor X er lavere alkylen, where X is lower alkylene,

karakterisert ved atl molekvivalent av p-klor-fenoxyisosmørsyre omsettes med 0,5 molekvivalent av et diamin med den generelle formel: characterized by atl mol equivalent of p-chloro-phenoxyisobutyric acid is reacted with 0.5 mol equivalent of a diamine with the general formula:

hvor X er som ovenfor angitt, og det således dannede salt utvinnes fra reaksjonsmediet. where X is as stated above, and the salt thus formed is recovered from the reaction medium.

2. Fremgangsmåte ifølge krav 1, 2. Method according to claim 1,

karakterisert ved at der som diamin anvendes ethylendiamin. characterized in that ethylenediamine is used as the diamine.

Claims

1. Setting device for driving anchor pins in the form of nails, bolts and the like, with or without a head or thread head, into hard materials, such as stone, concrete, iron, by means of a propellant-gas shock caused by the rapid combustion of a propellant charge , with a back-shock damping piston displaceably arranged in the longitudinal axis of the setting device, characterized in that the propellant charge (12) which is to be placed between the anchoring pin (43,

44) respectively between a sliding piece (13, 14) which serves to guide the anchoring pin (15) and the recoil dampening stamp (2, 3, 4), is displaceable in the set device in its longitudinal direction to an arbitrary ignition readiness position.

2. Setting device According to claim 1, characterized in that a variable he>n - i.e. replaceable mass (7) is connected in with the recoil damping element (2, 3, 4).

3. Setting device according to claim 1 or 1 2, characterized in that the front end (3) of the recoil damping piston is designed as a bearing for the charging sleeve (12) which, in turn, at ignition is in an axial position in the device which adjusts automatically by the length of the anchoring pin (15, 43, 44) to be driven in respectively with the addition of the push piece (13, 14).

4. Setting device According to one or more of the claims 1-3, with a limitation of the forward movement of the breech piece at a stop, characterized in that the stop (17) is arranged in such a way that the push piece (13, 14) in the stop position with its front end can protrude past the flat on the device that is brought to rest against the surface.

5. Set device according to one or more of the claims 1-4, characterized in that a recess (11) in the front end (3) of the recoil damping piston is designed to receive the charge sleeve (12) so that it can be inserted with the bottom in the pin driving direction.

6. Set device according to claim 5, characterized in that the bearing (11) for the explosive charge sleeve (12) passes into a mixed hole bore that serves as an expansion space for the gases.

7. Setting device according to one or more of the claims 1-6, characterized in that the bore (11) which accommodates the charge sleeve is designed in such a way that the sleeve will be clamped in the bore, e.g. in that the bore either has a shape that deviates from the cylindrical one, or the charge sleeve is non-round.

8. Setting device according to one or more of claims 1-7, characterized in that the striking surface of the igniter (18) has a size from 1/5 to the whole, preferably half, of the bottom surface of the charge sleeve (12).

9. Set device according to one or more of the claims 1-8 with exhaust openings arranged in the guide pipe which are released in the end position of the push piece, characterized in that the exhaust openings (22) open into a cavity (23) which surrounds the tube (1) and can be completely sealed and whose outer jacket (24) can be pulled off the device for cleaning the cavity.

10. Set device according to one or more of the claims 1-9, characterized in that the recoil damping piston length, to avoid unwanted ignition, is dimensioned in such a way that this piston with inserted charge sleeve (12) in its outermost forward thrust position does not can reach the push piece (13, 14) when this rests against its limiting stop (17), respectively the firing pin (18) arranged on this push piece.

11. Setting device According to one or more of the claims 1-10, characterized in that a disc (19) known per se is pushed onto the shaft of the associated pin, which serves to center the pin in the drive-in opening of the setting device and cooperates with devices arranged at this opening per se known, magnetically or mechanically acting holding means (31) in such a way that the anchoring pin is held with its tip directed essentially vertically towards the drive-in surface.

12. The setting device According to one or more of claims 1-11, characterized in that they e.g. holding means (31) designed as magnets or clamping springs allow a certain axial displacement of the pin (15) with attached disk (19).

13. Set device according to one or more of claims 1-12, characterized in that for limiting the movement of the rebound damping piston (2, 3) in the backward direction, a removable end piece (5) is arranged on the rear end of the guide tube (1) .

14. Set device according to one or more of the claims 1-13, characterized in that the 1 breech piece (5) movable recoil damping piston (2, 3, 4) can be replaced with a hammer-operable dabber (26) after the breech piece has been removed.