NO118745B

NO118745B -

Info

Publication number: NO118745B
Application number: NO162077A
Authority: NO
Inventors: W Nauta
Original assignee: Brochades Stheeman & Pharmacia
Priority date: 1965-03-15
Filing date: 1966-03-12
Publication date: 1970-02-09
Also published as: AT262269B; SE329844B; IL25356A

Description

Fremgangsmåte til fremstilling av forbindelser med dilaterende aktivitet på Process for the preparation of compounds with dilating activity on

koronaer a r teriene .coronary arteries.

Foreliggende oppfinnelse vedrører en fremgangsmåte til fremstilling av forbindelser med dilaterende aktivitet på koronararteri-ene, hvilke forbindelser har fSigende generelle formel: The present invention relates to a method for producing compounds with dilating activity on the coronary arteries, which compounds have the following general formula:

hvor R 2 og R^er lavere alkylgrupper og R^er et hydrogenatom eller en lavere alkylgruppe, samt syreaddisjonssalter av disse forbindelser, j where R 2 and R^ are lower alkyl groups and R^ is a hydrogen atom or a lower alkyl group, as well as acid addition salts of these compounds, j

Med den benyttede betegnelse "lavere alkyl" menes' rette eller forgrenede alkylgrupper med maksimalt 6 (fortrinnsvis Ikke fler enn 4) karbonatomer. The term "lower alkyl" used means straight or branched alkyl groups with a maximum of 6 (preferably no more than 4) carbon atoms.

Norsk patent nr. 105 353 vedrorer forbindelser med den generelle formel: Norwegian patent no. 105 353 relates to compounds with the general formula:

hvor R er en alkylenrest~'CH2^n~med ^~7karDonatomer, R-j^ er halogen eller en lavere alkyl-., alkoksy- eller alkylmercaptogruppe, A er en alkylenrest med en uforgrenet eller forgrenet kjede og X er en alkylamino-, dialkylamino-, piperidin-, pyrrolidin-, morfolin-eller piperazinrest, idet de heterocykliske rester eventuelt kan være substituert med en lavere alkylrest. Disse forbindelser er spesielt egnede for bruk i psykiatrisk farmakoterapi og har en sterk anti-Parkinson aktivitet, og det angis at forbindelsene bare har små virk-ninger på kretslopet. Det er nå funnet at de nye forbindelser, som inneholder en alkylsubstituert cykloheksylgruppe istedenfor gruppen where R is an alkylene residue~'CH2^n~with ^~7carDon atoms, R-j^ is halogen or a lower alkyl-., alkoxy- or alkyl mercapto group, A is an alkylene residue with an unbranched or branched chain and X is an alkylamino-, dialkylamino -, piperidine, pyrrolidine, morpholine or piperazine residue, the heterocyclic residues may optionally be substituted with a lower alkyl residue. These compounds are particularly suitable for use in psychiatric pharmacotherapy and have a strong anti-Parkinson activity, and it is stated that the compounds have only small effects on the circuit. It has now been found that the new compounds, which contain an alkyl substituted cyclohexyl group instead of the group

har hair

uventede farmakologiske egenskaper. De har dilaterende virkning på koronærarteriene koblet med en positiv inotropisk virkning og oker den refraktoriske periode. Videre har de sedative, hypnotiske og/ eller muskelrelakserende egenskaper. Deres meget lave;toksisitet samt kombinasjonen av sedative egenskaper og sterk koronaer dilaterende aktivitet, som er koblet med en positiv inotropisk virkning i terapeutisk aktive doser, gj6r forbindelsene meget verdifulle ved be-handling av koronære lidelser. De har også egenskaper som ligner det man finner hos kjente benzhydryletere som difenhydramin og orfena-drin, spesielt ved sistnevnte forbindelse. Foretrukne forbindelser unexpected pharmacological properties. They have a dilating effect on the coronary arteries coupled with a positive inotropic effect and increase the refractory period. Furthermore, they have sedative, hypnotic and/or muscle relaxant properties. Their very low toxicity as well as the combination of sedative properties and strong coronary dilating activity, which is coupled with a positive inotropic effect in therapeutically active doses, make the compounds very valuable in the treatment of coronary disorders. They also have properties similar to those found in known benzhydryl ethers such as diphenhydramine and orphenadrine, especially in the latter compound. Preferred connections

er de hvor R^og R^er metyl, samt deres syreaddisjonssalter. Som terapeutika kan forbindelsene med formel I brukes som så-dan eller som syreaddisjonssalter som inneholder farmasøytisk akseptable ikke-giftige anioner, f.eks. hydrohalidene, sulfatene, oksala- are those where R^ and R^ are methyl, as well as their acid addition salts. As therapeutics, the compounds of formula I can be used as such or as acid addition salts containing pharmaceutically acceptable non-toxic anions, e.g. the hydrohalides, sulfates, oxala-

tene, tartratene, fumaratene, acetatene, citratene, maleatene, succi-natene, laktatene og pamoatene. the tartrates, fumarates, acetates, citrates, maleates, succinates, lactates and pamoates.

IfSlge foreliggende oppfinnelse fremstilles forbindelsene med formel I ved å omsette et cykloheksanolderivat med den generelle According to the present invention, the compounds of formula I are prepared by reacting a cyclohexanol derivative with the general one

formel: formula:

med et aminoetylhalogenid med den generelle formel: with an aminoethyl halide of the general formula:

hvor R-p Rg, R^og R^har samme betydning som angitt foran, og hvor X er klor, brom eller jod. Reaksjonen utfores fortrinnsvis i nærvær av en kondenserende forbindelse som natriumamid, som kan brukes i ekvimolare mengder i forhold til cykloheksanolderivatet med formel II. Det er videre fordelaktig å oppvarme reaktantene i nærvær av et inert organisk løsningsmiddel som f.eks. en aromatisk hydrokarbon som ben-zen, toluen eller xylen. where R-p Rg, R^ and R^ have the same meaning as stated above, and where X is chlorine, bromine or iodine. The reaction is preferably carried out in the presence of a condensing compound such as sodium amide, which can be used in equimolar amounts in relation to the cyclohexanol derivative of formula II. It is further advantageous to heat the reactants in the presence of an inert organic solvent such as e.g. an aromatic hydrocarbon such as benzene, toluene or xylene.

Istedenfor aminoetylhalogenidet med formel III, så kan man anvende dens syreaddisjonssalter uten at dette har noen som helst innflytelse på reaksjonsbetingelsene eller på utbyttet. De ovenfor tilveiebragte baser kan om onskes, omsettes med en syre for dannelse av det tilsvarende syreaddisjonssalt. Instead of the aminoethyl halide of formula III, its acid addition salts can be used without this having any influence whatsoever on the reaction conditions or on the yield. The bases provided above can, if desired, be reacted with an acid to form the corresponding acid addition salt.

De fSigende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.

Eksempel IExample I

Til en suspensjon av 12 g finpulverisert natriumamid i ca.To a suspension of 12 g of finely powdered sodium amide for approx.

30 ml vannfri toluen ble det langsomt tilsatt en ISsning av 6I.5 g l-(o-tolyl)-2-metylcykloheksan-l-ol i ca. 100 ml vannfri toluen. Blandingen ble rort ved romtemperatur i ca. 30 minutter, hvoretter den ble oppvarmet under refluks i 4 timer. 32»15 g P-dimetylamino-etylklorid ble deretter tilsatt, og blandingen ble rort ved romtemperatur i 1 time, hvoretter den ble kokt under refluks i ca. l6 timer. 30 ml of anhydrous toluene was slowly added with a solution of 61.5 g of 1-(o-tolyl)-2-methylcyclohexan-1-ol in approx. 100 ml anhydrous toluene. The mixture was stirred at room temperature for approx. 30 minutes, after which it was heated under reflux for 4 hours. 32.15 g of β-dimethylaminoethyl chloride was then added, and the mixture was stirred at room temperature for 1 hour, after which it was boiled under reflux for approx. l6 hours.

Etter avkjSling ble blandingen heilt over i vann, toluen-laget ble separert, og vannlaget ble ekstrahert med dietyleter. Toluen og eterlosningene ble slått sammen, vasket med vann og torket med natriumsulfat. Etter filtrering ble dietyleter og toluen destil-lert av, og innholdet av l-(o-tolyl)-2-metylcykloheks-l-yl P-di-metylaminoetyl i residumet ble bestemt ved titrering. Den beregnede mengde hydrogenklorid i dietyleter ble deretter tilsatt, og det ut-felte hydroklorid ble frafiltrert og deretter vasket med dietyleter. Man oppnådde 66.6 g av produktet, smeltepunkt 162.5°-l64°C. After cooling, the mixture was poured into water, the toluene layer was separated, and the water layer was extracted with diethyl ether. The toluene and ether solutions were combined, washed with water and dried with sodium sulfate. After filtration, diethyl ether and toluene were distilled off, and the content of 1-(o-tolyl)-2-methylcyclohex-1-yl P-dimethylaminoethyl in the residue was determined by titration. The calculated amount of hydrogen chloride in diethyl ether was then added, and the precipitated hydrochloride was filtered off and then washed with diethyl ether. 66.6 g of the product were obtained, melting point 162.5°-164°C.

Eksempel IIExample II

Ved å bruke den generelle fremgangsmåte som er beskrevet i eksempel I, men ved å bruke forskjellige l-(o-alkylfenyl)-2-alkyl-cykloheksan-l-oler istedenfor den angitte 1-(o-tolyl)-2-metylcyklo-heksan-l-ol, ble de folgende 1-(o-alkylfenyl)-2-alkylcykloheksan-l-yl P-dimetylaminoetyletere oppnådd i form av sine hydroklorider. Using the general procedure described in Example I, but using different 1-(o-alkylphenyl)-2-alkyl-cyclohexan-1-ols instead of the stated 1-(o-tolyl)-2-methylcyclo- hexan-1-ol, the following 1-(o-alkylphenyl)-2-alkylcyclohexan-1-yl P-dimethylaminoethyl ethers were obtained in the form of their hydrochlorides.

De ifolge oppfinnelsen fremstilte forbindelser kan anvendes The compounds produced according to the invention can be used

i farmasøytiske preparater og disse kan være i samme' form som det man vanligvis anvender i forbindelser med terapeutisk aktive forbindelser, men de foretrukne typer er de som egner seg for oral tilforsel, spesielt tabletter, piller og kapsler som inneholder den aktive for-bindelsen. Tablettene og pillene kan sammensettes på vanlig måte in pharmaceutical preparations and these can be in the same form as that which is usually used in compounds with therapeutically active compounds, but the preferred types are those suitable for oral administration, especially tablets, pills and capsules containing the active compound. The tablets and pills can be compounded in the usual way

med ett eller flere farmakologisk akseptable fortynningsmidler som f.eks. laktose eller stivelse, og kan videre innbefatte forbindelser av smorende natur, f.eks. kalsiumstearat. Kapsler som fremstilles av absorberbart materiale, f.eks. gelatin, kan inneholde den aktive forbindelse alene eller i blanding med et fast eller flytende for-tynningsmiddel. Flytende preparater kan være i form av suspensjoner, emulsjoner, siruper eller eliksirer av den aktive forbindelse i vann eller et annet flytende medium som vanligvis brukes ved fremstilling av oralt akseptable farmasoytiske preparater, som f.eks. flytende parafin eller en eller annen form for sirup. Videre kan man frem-stille preparater som egner seg for parenteral tilforsel, dvs. suspensjoner, emulsjoner eller losninger av den aktive forbindelse i sterilt vann, eller en organisk væske som vanligvis brukes ved inji-serbare preparater, f.eks. en vegetabilsk olje som olivenolje, eller en steril losning i et organisk løsningsmiddel. with one or more pharmacologically acceptable diluents such as e.g. lactose or starch, and may further include compounds of a lubricating nature, e.g. calcium stearate. Capsules made of absorbable material, e.g. gelatin, may contain the active compound alone or in mixture with a solid or liquid diluent. Liquid preparations can be in the form of suspensions, emulsions, syrups or elixirs of the active compound in water or another liquid medium which is usually used in the preparation of orally acceptable pharmaceutical preparations, such as e.g. liquid paraffin or some form of syrup. Furthermore, preparations suitable for parenteral administration can be prepared, i.e. suspensions, emulsions or solutions of the active compound in sterile water, or an organic liquid which is usually used for injectable preparations, e.g. a vegetable oil such as olive oil, or a sterile solution in an organic solvent.

Claims

1. Continuous method for en-dothermal reduction of finely divided ores, e.g. low-grade iron ore, extensive treatment

ling in fluidized layers in three zones, one preheating layer, one combustion layer where the heat necessary for the reduction is provided, and one reduction layer where the hot ore is fluidized in a reducing atmosphere, characterized by the fact that the combustion layer is inserted in the process between the preheating layer and the reduction layer, and that only a part (e.g. half) of the ore that comes from the preheating layer is heated in the combustion zone, whereby the temperature in this zone can be kept sufficiently high in an economical way for a complete and efficient combustion of the gas or oil fuel , while the rest of the ore from the preheating layer is directly supplied to the reduction zone where it is brought to the required reduction temperature by heat transfer from the hot ore that the reduction zone receives from the combustion zone.

2. Method as stated in claim 1, characterized in that the regulation of the final temperature in the reduction zone is carried out by regulating the proportions of ore that are brought together in this zone.

3. Method as stated in claim 1 or 2, characterized in that hot combustible reducing gas is used for fluidizing the reduction layer and the formation of the reducing atmosphere therein, and that this gas, after it has left the reduction layer, upon addition of oxygen (air) is prepared to burn so that combustion can take place in the combustion layer.

4. Apparatus for carrying out a method as stated in one of the claims 1-3, comprising a multi-stage reactor which is provided with the usual devices for feeding and maintaining the three layers and with the combustion layer lying between the preheating layer and the underlying reduction layer, characterized by a dividing wall which divides the preheating layer into two compartments, one which is in direct material-transferring connection with the combustion layer and one which is in direct material-releasing connection with the reduction layer by means of a downpipe led through the combustion layer as well as by means of individual adjustment of the feed quantity to the two compartments and thereby also of the discharge quantity from these.