NO791222L - PROCEDURE FOR THE PREPARATION OF TETRAHYDROALSTONE INDIVATIVES - Google Patents

PROCEDURE FOR THE PREPARATION OF TETRAHYDROALSTONE INDIVATIVES

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Publication number
NO791222L
NO791222L NO79791222A NO791222A NO791222L NO 791222 L NO791222 L NO 791222L NO 79791222 A NO79791222 A NO 79791222A NO 791222 A NO791222 A NO 791222A NO 791222 L NO791222 L NO 791222L
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Norway
Prior art keywords
radical
acid
tetrahydroalstonine
compounds
carbon atoms
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NO79791222A
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Norwegian (no)
Inventor
Henry Najer
Bernard Mompon
Braham Schroot
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Synthelabo
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Priority claimed from FR7811026A external-priority patent/FR2422664A1/en
Application filed by Synthelabo filed Critical Synthelabo
Publication of NO791222L publication Critical patent/NO791222L/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/26Psychostimulants, e.g. nicotine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid

Description

Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av tetrahydroalstoninderivater, og deres addisjonssalter med farmasøytisk tålbare syrer. The present invention relates to a method for the production of tetrahydroalstonine derivatives, and their addition salts with pharmaceutically acceptable acids.

Tetrahydroalstonin, som er et naturprodukt som kan fremstilles f.eks. fra Catharanthus lanceus og fra Rauwolfia vomitoria, er kjent og dets biologiske aktivitet er beskrevet i fransk patentskrift nr. 1.397.537 og belgisk patentskrift nr. 834.585. Tetrahydroalstonin, which is a natural product that can be produced e.g. from Catharanthus lanceus and from Rauwolfia vomitoria, is known and its biological activity is described in French Patent Document No. 1,397,537 and Belgian Patent Document No. 834,585.

Oppfinnelsen vedrorer således en fremgangsmåte for fremstilling av forbindelser med formel (I) The invention thus relates to a method for producing compounds of formula (I)

hvori in which

er hydroksyalkyl, alkyl eller alkoksykarbonyl, eller et is hydroxyalkyl, alkyl or alkoxycarbonyl, or et

hydrogenatom,hydrogen atom,

R2 er hydroksyl, rett eller forgrenet alkoksy med 1 til 6 R 2 is hydroxyl, straight or branched 1 to 6 alkoxy

karbonatomer som kan bære halogensubstituenter, eller carbon atoms which may carry halogen substituents, or

cykloalkylalkoksy, cykloalkoksy, alkoksy som kan bære en piperidino-, morfolino-, piperazino- eller pyrrolidino-gruppe/ eller en dialkylaminoalkoksygruppe, amino, alkyl-amino, dialkylamino, cykloalkylamino, eller et radikal cycloalkylalkyloxy, cycloalkyloxy, alkyloxy which may bear a piperidino, morpholino, piperazino or pyrrolidino group/ or a dialkylaminoalkyloxy group, amino, alkylamino, dialkylamino, cycloalkylamino, or a radical

OMe (Me = alkalimetall eller jordalkalimetall).OMe (Me = alkali metal or alkaline earth metal).

med unntagelse av forbindelsen hvori R1= H og R2= CH^O,with the exception of the compound in which R1= H and R2= CH^O,

idet de nevnte alkylradikaler og alkoksyradikaler har 1 til 6 karbonatomer, cykloalkylradikalene og cykloalkoksyradikalene har 3 til 6 karbonatomer, såvel som deres addisjonssalter med farmasoytisk tålbare syrer. the aforementioned alkyl radicals and alkoxy radicals having 1 to 6 carbon atoms, the cycloalkyl radicals and the cycloalkoxy radicals having 3 to 6 carbon atoms, as well as their addition salts with pharmaceutically acceptable acids.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at en syre med formel (I), hvori R^ = hydrogen og R2= OH fremstilles ved forsepning av tetrahydroalstonin hvoretter de onskede estere med formel (I) fremstilles på i og for seg kjente måter ved forestring av syren og/eller en av dens funksjonelle derivater eller ved transforestring av tetrahydroalstonin, idet onskede amider (I) fremstilles ved amidering av syren eller en av dens funksjonelle derivater, og derivatene (I) som bærer en substituent i 1-stillingen oppnås ved å gå ut fra tilsvarende forbindelser (I) hvori R^= H ved formulering eller ved reaksjon med et alkylhalogenid eller med alkoksykarbonylhalogenid. The peculiarity of the method according to the invention is that an acid of formula (I), in which R^ = hydrogen and R 2 = OH is prepared by saponification of tetrahydroalstonine, after which the desired esters of formula (I) are prepared in known ways by esterification of the acid and/or one of its functional derivatives or by transesterification of tetrahydroalstonine, the desired amides (I) being prepared by amidation of the acid or one of its functional derivatives, and the derivatives (I) bearing a substituent in the 1-position are obtained by starting from corresponding compounds (I) in which R^= H by formulation or by reaction with an alkyl halide or with an alkoxycarbonyl halide.

Forbindelsene (I) er terapeutisk aktive med virkning på sentralnervesystemet, som antianoksigene forbindelser og som psykotrope forbindelser, spesielt som antidepresiva. The compounds (I) are therapeutically active with effects on the central nervous system, as anti-anoxic compounds and as psychotropic compounds, especially as antidepressants.

De folgende eksempler illustrerer oppfinnelsen. Analyser og spektra IR, RMN, UV og masse bekrefter strukturen av forbindelsene. The following examples illustrate the invention. Analyzes and spectra IR, RMN, UV and mass confirm the structure of the compounds.

THA = tetrahydroalstonin.THA = tetrahydroalstonine.

EKSEMPEL 1 16,17-didehydro-l9a-metyl-oksayohimban-16-karboksylsyre og dets hydroklorid EXAMPLE 1 16,17-didehydro-19α-methyl-oxayohimbane-16-carboxylic acid and its hydrochloride

30 g THA innfores i en vandig losning av etanolisk kalium hydroksyd (21 g KOH, 600 ml vann og 600 ml etanol). Blandingen kokes under tilbakelop i 2,5 time. 30 g of THA are introduced into an aqueous solution of ethanolic potassium hydroxide (21 g of KOH, 600 ml of water and 600 ml of ethanol). The mixture is boiled under reflux for 2.5 hours.

Etanol fjernes ved avdestillering under redusert trykk inntil det oppnås en rest som inntar omtrent 1/5 av det opprinnelige volum. Resten opploses ill vann, opplosningen nøytraliseres ved hjelp av 6N saltsyre inntil pH = 7 og ekstraheres 6 ganger med 500 ml kloroform. Kloroformfåsene oppnådd ved dekantering forenes, vaskes med vann og torkes over vannfritt natriumsulfat. Ethanol is removed by distillation under reduced pressure until a residue is obtained which occupies approximately 1/5 of the original volume. The residue is dissolved in water, the solution is neutralized with 6N hydrochloric acid until pH = 7 and extracted 6 times with 500 ml of chloroform. The chloroform fractions obtained by decantation are combined, washed with water and dried over anhydrous sodium sulfate.

Etter filtrering fjernes kloroform på vannbad ved 40°C under redusert trykk. After filtration, chloroform is removed in a water bath at 40°C under reduced pressure.

Det oppnås 25 g av syren (I).25 g of the acid (I) is obtained.

Man fremstiller hydrokloridet av syren ved oppløsning av syrenThe hydrochloride of the acid is produced by dissolving the acid

i kloroform og gjennomføring av en hydrogenkloridgass-strom gjennom opplosningen. in chloroform and passing a current of hydrogen chloride gas through the solution.

Smp. = 225°C med spalting, [a]^<5>= -26,6° (C = 0,6; EtOH) Temp. = 225°C with cleavage, [a]^<5>= -26.6° (C = 0.6; EtOH)

EKSEMPEL 2 Isobutylester av 16,17-didehydro-l9a-metyl-oksayohimban-16-karboksylsyre og dens h<y>droklorid EXAMPLE 2 Isobutyl ester of 16,17-didehydro-19a-methyl-oxayohimbane-16-carboxylic acid and its hydrochloride

9 g av syren fra eksempel 1 opploses i 300 ml vannfri kloroform og fri for alkohol. 9 g of the acid from example 1 are dissolved in 300 ml of anhydrous chloroform and free of alcohol.

Det tilsettes på en gang 2,35 ml pyridin nylig destillert over kaliumhydroksyd. 2.35 ml of pyridine freshly distilled over potassium hydroxide are added at once.

Det tilsettes 2,5 ml oksalylklorid i oppløsning i 10 ml vannfri kloroform. 2.5 ml of oxalyl chloride in solution in 10 ml of anhydrous chloroform is added.

Reaksjonsblandingen settes deretter bort i 3 timer under The reaction mixture is then set aside for 3 hours below

omroring ved omgivelsenes temperatur.stirring at ambient temperature.

Til opplosningen av det derved dannede syreklorid tilsettesThe acid chloride thus formed is added to the solution

30 ml nydestillert isobutylalkohol. Omroringen ved omgivelsenes temperatur fortsettes i 1 time. 30 ml freshly distilled isobutyl alcohol. Stirring at ambient temperature is continued for 1 hour.

Det tilsettes 300 ml destillert vann og det inndampes helt til torrhet. Til den oljeaktige rest tilsettes 1000 ml vann, blandingen gjores alkalisk ved hjelp av en 10% ammoniakklosning og ekstraheres 4 ganger med 400 ml kloroform. Kloroformfåsene oppnådd ved dekantering forenes, vaskes med vann og torkes deretter over vannfritt natriumsulfat. Etter filtrering fjernes kloroform på vannbad ved 40°C under redusert trykk. 300 ml of distilled water is added and evaporated to dryness. 1000 ml of water is added to the oily residue, the mixture is made alkaline using a 10% ammonia solution and extracted 4 times with 400 ml of chloroform. The chloroform fractions obtained by decantation are combined, washed with water and then dried over anhydrous sodium sulfate. After filtration, chloroform is removed in a water bath at 40°C under reduced pressure.

Den oppnådde rest gjores opploselig i 300 ml kloroform ved omroring ved 50°C i nærvær av 2 g aktivert vegetabilsk kull. Etter filtrering inndampes til torrhet og resten opptas i en minste mengde isobutanol og tilsettes en vannfri opplosning av saltsyreeter til pH 1. Man avsuger de dannede krystaller på filter. The obtained residue is made soluble in 300 ml of chloroform by stirring at 50°C in the presence of 2 g of activated vegetable charcoal. After filtration, the mixture is evaporated to dryness and the residue is taken up in a small amount of isobutanol and an anhydrous solution of hydrochloric acid ether is added to pH 1. The formed crystals are filtered off with suction.

Det oppnås 6 g av hydrokloridet av isobutylesteren.6 g of the hydrochloride of the isobutyl ester are obtained.

Smp. = 250°C med spalting, ["cj^<5>= -3,8° (c=l; CHC13).Temp. = 250°C with cleavage, ["cj^<5>= -3.8° (c=1; CHC13).

EKSEMPEL 3 Morlolinetylester av 16,17-didehydro-lQa-metyl-oksayohimban-ie-karboksylsyre og dens hydroklorid. EXAMPLE 3 Morloline ethyl ester of 16,17-didehydro-1α-methyl-oxayohimbane-carboxylic acid and its hydrochloride.

10,56 g THA opploses i 400 ml vannfri benzen destillert over kalsiumklorid. 10.56 g of THA are dissolved in 400 ml of anhydrous benzene distilled over calcium chloride.

Det tilsettes 690 mg metallisk natrium på forhånd vasket med vannfri benzen under omroring og under argonatmosfære. 690 mg of metallic sodium previously washed with anhydrous benzene are added while stirring and under an argon atmosphere.

Reaksjonsblandingen får reagere i omtrent 10 min. og tilsettes i lopet av 15 min. 4,3 g morfolino-etanol på forhånd opplost i 20 ml vannfri benzen. Blandingen kokes under tilbakelop i 5 timer og 30 min. under argon i nærvær av molekylsikt. The reaction mixture is allowed to react for approximately 10 min. and added over the course of 15 min. 4.3 g of morpholino ethanol previously dissolved in 20 ml of anhydrous benzene. The mixture is boiled under reflux for 5 hours and 30 minutes. under argon in the presence of molecular sieves.

Etter å ha fjernet overskudd av natrium ved filtrering tilsettesAfter removing excess sodium by filtration is added

1 1 vann og blandingen ekstraheres med benzen. Den vasked med 100 ml vann, torkes over natriumsulfat og inndampes til torrhet. 1 1 water and the mixture is extracted with benzene. It is washed with 100 ml of water, dried over sodium sulphate and evaporated to dryness.

Man opploser det oppnådde produkt i metanol hvoretter saltsyre-eteren tilsettes. The product obtained is dissolved in methanol, after which the hydrochloric acid ether is added.

Hydrokloridet krystalliserer.The hydrochloride crystallizes.

Smp. = 305°C, [a]^<5>= -12,6° (c=0,54; H20) Temp. = 305°C, [a]^<5>= -12.6° (c=0.54; H2O)

EKSEMPEL 4 Cyklopropylamidet av 16,17-didehydro-19a-metyl-oksayohimban-16-karboksylsyre og dets hydroklorid. EXAMPLE 4 The cyclopropylamide of 16,17-didehydro-19α-methyl-oxayohimbane-16-carboxylic acid and its hydrochloride.

10,5 g av syren fra eksempel 1 opploses i 350 ml vannfri kloroform som er fri for alkohol. 10.5 g of the acid from example 1 is dissolved in 350 ml of anhydrous chloroform which is free of alcohol.

På en gang tilsettes 2,8 ml av pyridin nettopp destillert over kaliumhydroksyd hvoretter det tilsettes 3 ml av oksalylkloridet på forhånd opplost i 12 ml vannfri kloroform. 2.8 ml of pyridine just distilled over potassium hydroxide are added at once, after which 3 ml of the oxalyl chloride previously dissolved in 12 ml of anhydrous chloroform are added.

Reaksjonsblandingen settes bort i 3 timer ved omgivelsenes temperatur under omroring. The reaction mixture is set aside for 3 hours at ambient temperature with stirring.

Til opplosningen av syrekloridet dannet på denne måte tilsettes 20 ml cyklopropylamin i lopet av 15 min. og blandingen holdes under omroring i ytterligere 30 min. etter avsluttet tilsetning. To the solution of the acid chloride formed in this way, 20 ml of cyclopropylamine are added over the course of 15 minutes. and the mixture is kept under stirring for a further 30 min. after the addition has been completed.

Man tilsetter 1 1 vann. Det organiske lag og den vandige rest-fase ekstraheres 3 ganger med 500 ml kloroform. De fire organiske faser slås sammen, vaskes med vann og torkes over vannfritt natriumsulfat. 1 1 water is added. The organic layer and the aqueous residual phase are extracted 3 times with 500 ml of chloroform. The four organic phases are combined, washed with water and dried over anhydrous sodium sulfate.

Etter filtrering fjernes kloroform på vannbad ved 40°C under redusert trykk. After filtration, chloroform is removed in a water bath at 40°C under reduced pressure.

Resten opploses i en minst mengde metanol (omtrent 20 ml) og tilsettes vannfri saltsyreeter til pH = 1. The residue is dissolved in a minimum amount of methanol (approximately 20 ml) and anhydrous hydrochloric acid ether is added to pH = 1.

Det dannede bunnfall isoleres og torkes.The formed precipitate is isolated and dried.

Man oppnår hydrokloridet av amidet.The hydrochloride of the amide is obtained.

Smp. = 225 - 228°C, [af]^<5>= -59,7° (c=l; DMF)Temp. = 225 - 228°C, [af]^<5>= -59.7° (c=1; DMF)

EKSEMPEL 5 Metylesteren av l-hydroksymetyl-16,17-didehydro-19a-metyloksayohimban-16-karboksylsyre EXAMPLE 5 The methyl ester of 1-hydroxymethyl-16,17-didehydro-19a-methyloxayohimbane-16-carboxylic acid

Til 5 g THA opplost i 50 ml kloroform tilsettes 200 ml av en vandig losning av formaldehyd 30% i nærvær av 1 ml eddiksyre. To 5 g of THA dissolved in 50 ml of chloroform, 200 ml of an aqueous solution of formaldehyde 30% in the presence of 1 ml of acetic acid is added.

Man "holder blandingen ved 50°C under omroring i 2 timer hvoretter reaksjonsblandingen settes bort ved omgivelsenes temperatur i omtrent 15 timer. The mixture is kept at 50°C with stirring for 2 hours, after which the reaction mixture is left at ambient temperature for approximately 15 hours.

300 ml destillert vann helles over reaksjonsblandingen som ekstraheres 4 ganger med metylenklorid, hvoretter den vaskes med vann, torkes over natriumsulfat og inndampes til torrhet. 300 ml of distilled water is poured over the reaction mixture which is extracted 4 times with methylene chloride, after which it is washed with water, dried over sodium sulphate and evaporated to dryness.

Blandingen kromatograferes gjennom en kolonne av silikagel ved hjelp av ren kloroform, deretter ved hjelp av en blanding kloroform/metanol (99/1) som eluerer 3 g av det onskede produkt. The mixture is chromatographed through a column of silica gel using pure chloroform, then using a mixture of chloroform/methanol (99/1) which elutes 3 g of the desired product.

Produktet krystalliseres i en blanding av metylenklorid/eter etter behandling med vegetabilsk kullæ The product is crystallized in a mixture of methylene chloride/ether after treatment with vegetable charcoal

Smp. = 171°C, [a]^<5>= -186° (c=l; CHC13)Temp. = 171°C, [a]^<5>= -186° (c=1; CHC13)

EKSEMPEL 6 MetyleSfeer av l-metoksykarbonyl-16,17-didehydro-19 a-me tyl-oksayohimban-16-karboksylsyre 14 g tetrahydroalstonin opplost i 120 ml dimetylsylfoksyd tilsettes 3,84 g natriumhydrid under omroring og under argon. EXAMPLE 6 Methyl spheres of 1-methoxycarbonyl-16,17-didehydro-19α-methyl-oxayohimbane-16-carboxylic acid 14 g of tetrahydroalstonine dissolved in 120 ml of dimethylsulphoxide are added to 3.84 g of sodium hydride while stirring and under argon.

Man tilsetter deretter 7,52 g metylklorformiat ved hjelp av en dråpetrakt under omroring og avkjoling ved en temperatur omtrent +5°C. Reaksjonsblandingen etterlates under omroring i 1 time og tilsettes sakte vann (omtrent 1 1). Eteren ekstraheres 4 ganger, vaskes med vann, torkes over natriumsulfat og inndampes deretter til torrhet. 7.52 g of methyl chloroformate are then added using a dropping funnel while stirring and cooling at a temperature of approximately +5°C. The reaction mixture is left under stirring for 1 hour and water is slowly added (approximately 1 1). The ether is extracted 4 times, washed with water, dried over sodium sulphate and then evaporated to dryness.

Produktet krystalliserer fra en blanding av metyfcenklorid/metanol (1/1). The product crystallizes from a mixture of methyphene chloride/methanol (1/1).

Smp. = 183°C, [a]^<5>= -276,8° (c=l,17; CHC13) Temp. = 183°C, [α]^<5>= -276.8° (c=1.17; CHCl 3 )

Forbindelsene fremstilt ved fremgangsmåten i henhold til oppfinnelsen og som utgjor eksempler på denne er gjengitt i den etterfolgende tabell (I). The compounds produced by the method according to the invention and which constitute examples thereof are reproduced in the following table (I).

HC1 = hydrokloridet.HC1 = the hydrochloride.

EKSEMPEL 7 Etylamidet av l-etoksykarbonyl-16,17-didehydro-19a-metyl-oksayohimban-16-karboksylsyre EXAMPLE 7 The ethyl amide of 1-ethoxycarbonyl-16,17-didehydro-19a-methyl-oxayohimbane-16-carboxylic acid

Ved hjelp av en dråpetrakt tilsettes 7,4 g av etylamidet av 16,17-didehydro-19a-metyl-oksayohimban-16-karboksylsyre i opplosning i 70 ml DMF i en kolbe inneholdende 2 g natriumhydrid. Operasjonen gjennomføres under argon under omroring. By means of a dropping funnel, 7.4 g of the ethyl amide of 16,17-didehydro-19a-methyl-oxayohimbane-16-carboxylic acid in solution in 70 ml of DMF are added to a flask containing 2 g of sodium hydride. The operation is carried out under argon with stirring.

Blandingen får reagere i 30 min. hvoretter man dråpevis tilsetter 4 ml etylkloroformiat. The mixture is allowed to react for 30 min. after which 4 ml of ethyl chloroformate is added dropwise.

Blandingen avkjoles på isbad og tilsettes vann. Man ekstraherer 5 ganger med eter, vasker med vann, torker over natriumsulfat og inndampes til torrhet. Eterekstrakten opploses i en blanding av kloroform og etanol som inndampes og settes bort i kulden. Man oppnår det krystalliserte produkt. The mixture is cooled in an ice bath and water is added. It is extracted 5 times with ether, washed with water, dried over sodium sulphate and evaporated to dryness. The ether extract is dissolved in a mixture of chloroform and ethanol which is evaporated and put away in the cold. The crystallized product is obtained.

Smp. = 240°C Temp. = 240°C

De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser ble underkastet forskjellige farmakologiske forsok. The compounds that can be prepared by the method according to the invention were subjected to various pharmacological tests.

Forbindelsene ble underkastet hypobar anoxia-test med mus og test med hensyn til innvirkning på varigheten av sovn indusert ved hjelp av natrium=-4-hydroksybutyrat i curarisert rotte. The compounds were subjected to the mouse hypobaric anoxia test and tested for effects on the duration of sleep induced by sodium=-4-hydroxybutyrate in the curarized rat.

HYPOBAR ANOXIAHYPOBARIC ANOXIA

Mus av stammen CD1 holdes i en atmosfære med redusert oksygen-innhold ved etablering av et partielt undertrykk (190 mm kvikksolv tilsvarende 5,25% oksygen). Mice of strain CD1 are kept in an atmosphere with reduced oxygen content by establishing a partial negative pressure (190 mm Hg corresponding to 5.25% oxygen).

Overlevelsestiden for dyrene noteres. Denne tid forlenges ved hjelp av midler som er i stand til å favorisere oksygenering i vev og spesielt i hjernen. De undersokte forbindelser tilfores i flere doser intraperitonealt 10 min. for forsoket. Den prosentvise okning av overlevelsestiden i forhold til verdier oppnådd i kontrolldyr beregnes. Den midlere aktive dose (DAM) somcker overlevelsestiden med 100% bestemmes grafisk. The survival time of the animals is noted. This time is extended using agents that are able to favor oxygenation in tissues and especially in the brain. The investigated compounds are administered in several doses intraperitoneally for 10 min. too attempted. The percentage increase in survival time compared to values obtained in control animals is calculated. The mean active dose (MAD) that increases the survival time by 100% is determined graphically.

DAM for forbindelsene fremstilt i henhold til oppfinnelsen varierer fra 10 til 60 mg/kg tilfort i.p. DAM for the compounds prepared according to the invention varies from 10 to 60 mg/kg administered i.p.

INNVIRKNING PÅ VARIGHETEN AV " SOVN" INFLUENCE ON THE DURATION OF "SLEEP"

Denne virkning bestemmes ved innvirkningen av forbindelsene på varigheten av den "sovn" som innfores av natrium-4-hydroksy-butyrat (GHB) i rotter curarisert under kunstig åndedrett hvori elektrokortikografisk aktivitet registreres ved hjelp av kortikale elektroder. This effect is determined by the effect of the compounds on the duration of the "sleep" induced by sodium 4-hydroxybutyrate (GHB) in rats curarized under artificial respiration in which electrocorticographic activity is recorded by means of cortical electrodes.

De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser nedsetter den totale varighet av sovnen med 20 til 40% i forhold til kontrollforsok. The compounds that can be produced by the method according to the invention reduce the total duration of sleep by 20 to 40% compared to the control experiment.

Giftigheten av forbindelsene ble bestemt ved intraperitoneal tilforsel i mus. The toxicity of the compounds was determined by intraperitoneal administration in mice.

LD 50 varierer fra 300 til 1.000 mg/kg.LD 50 varies from 300 to 1,000 mg/kg.

Den farmakologiske undersøkelse av forbindelsene viser at de er aktive ved prover med hypobar anoxia i mus samtidig med at de har liten giftighet og at de utover en betraktelig virkning påvist ved forsok med "sovn" indusert ved hjelp av natrium-4-hydroksy-butyrat. The pharmacological examination of the compounds shows that they are active in tests with hypobaric anoxia in mice while at the same time having little toxicity and that they exceed a considerable effect demonstrated in experiments with "sleep" induced by means of sodium-4-hydroxy-butyrate.

Forbindelsene har samtidig en antianoxia-virkning og enThe compounds simultaneously have an antianoxia effect and a

psykotrop virkning, og kan anvendes i terapien for behandling av nedsatt aktivitet, spesielt i kampen mot adferdsforstyrrelser medfort av vasculære hjerneskader og cerebralselerose innen geriatrien, såvel som for behandling av bevisstløshet som skyldes kranieskader, og ved behandling av depressive tilstander. psychotropic effect, and can be used in the therapy for the treatment of reduced activity, especially in the fight against behavioral disorders accompanied by vascular brain damage and cerebral sclerosis in geriatrics, as well as for the treatment of unconsciousness due to skull injuries, and in the treatment of depressive states.

Forbindelsene kan anvendes enten alene eller sammen med vanlige tilsetningsmidler for tilforsel, spesielt oral eller parenteral tilforsel, og samlet dose utgjor fra 10 til 200 mg. The compounds can be used either alone or together with usual additives for administration, especially oral or parenteral administration, and the total dose is from 10 to 200 mg.

Claims (1)

Fremgangsmåte for fremstilling av tetrahydroalstoninderivater med den generelle formel (I)Process for the preparation of tetrahydroalstonine derivatives of the general formula (I) hvori er et hydroksyalkyl-, alkyl- eller alkoksykarbonyl-radikal eller et hydrogenatom, R2 er et hydroksylradikal, eller et rett eller forgrenet alkoksyradikal med 1 til 6 karbonatomer og som kan være halogensubstituert, et cykloalkylalkoksyradikal, et cykloalkoksyradikal, et alkoksyradikal som bærer en piperidino-, morfolino-, piperazino- eller pyrrolidino-gruppe, et dialkylaminoalkoksyradikal, et aminoradikal, et alkylaminoradikal, et dialkylaminoradikal, et cykloalkylaminoradikal, eller et radikal OMe (Me=alkalimetall eller jordalkalimetall), med unntagelse av den forbindelse hvori R^ =H og R^ CH^ O, idet alkyl- eller alkoksy-radikalene har 1 til 6 karbonatomer, cykloalkyl- og cykloalkoksy-radikalene har 3 til 6 karbonatomer, såvel som addisjonssalter derav med farmasøytisk tålbare syrer, karakterisert ved at man fremstiller syren (I) hvori R^ =H og R2 =OH ved forsepning av tetrahydroalstonin, deretter fremstiller esterne (I) ved hjelp av kjente metoder, spesielt ved forestring av syren eller et av dens funksjonelle derivater eller ved transforestring av tetrahydroalstonin, hvoretter amidene (I) enten fremstilles ved amidering av syren eller en av dens funksjonelle derivater, og forbindelsene (I) som bærer en substituent i 1-stillingen fremstilles ved å gå ut fra tilsvarende forbindelser (I) hvori R^ er H ved formylering eller ved reaksjon med et alkylhalogenid eller alkoksykarbonyl-' halogenid. in which is a hydroxyalkyl, alkyl or alkoxycarbonyl radical or a hydrogen atom, R2 is a hydroxyl radical, or a straight or branched alkoxy radical with 1 to 6 carbon atoms and which may be halogen-substituted, a cycloalkyl alkoxy radical, a cycloalkoxy radical, an alkoxy radical bearing a piperidino, morpholino, piperazino or pyrrolidino group, a dialkylaminoalkoxy radical, an amino radical, an alkylamino radical, a dialkylamino radical, a cycloalkylamino radical, or a radical OMe (Me=alkali metal or alkaline earth metal), with the exception of the compound in which R^ =H and R^ CH^ O, the alkyl or alkoxy radicals having 1 to 6 carbon atoms, The cycloalkyl and cycloalkoxy radicals have 3 to 6 carbon atoms, as well as addition salts thereof with pharmaceutically acceptable acids, characterized by preparing the acid (I) in which R^ =H and R2 =OH by saponification of tetrahydroalstonine, then prepare the esters (I) using known methods, in particular by esterification of the acid or one of its functional derivatives or by transesterification of tetrahydroalstonine, after which the amides (I) are either prepared by amidation of the acid or one of its functional derivatives, and the compounds (I) which carry a substituent in the 1-position are prepared by starting from corresponding compounds (I) in which R^ is H by formylation or by reaction with an alkyl halide or alkoxycarbonyl halide.
NO79791222A 1978-04-14 1979-04-10 PROCEDURE FOR THE PREPARATION OF TETRAHYDROALSTONE INDIVATIVES NO791222L (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7811026A FR2422664A1 (en) 1978-04-14 1978-04-14 Tetra:hydro:alstonine ester and amide derivs. - with anti:anoxic, psychotropic and antidepressant activity (BE 15.10.79)
FR7906055A FR2450835A2 (en) 1978-04-14 1979-03-09 TETRAHYDROALSTONIN DERIVATIVES AND THEIR THERAPEUTIC APPLICATION

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DE (1) DE2914805A1 (en)
DK (1) DK149279A (en)
ES (1) ES479540A1 (en)
FI (1) FI791194A (en)
FR (1) FR2450835A2 (en)
GB (1) GB2018751A (en)
GR (1) GR66991B (en)
IL (1) IL57061A0 (en)
IT (1) IT1111923B (en)
LU (1) LU81145A1 (en)
NL (1) NL7902958A (en)
NO (1) NO791222L (en)
PT (1) PT69487A (en)

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FR2451376B1 (en) * 1979-03-14 1986-04-18 Fabre Sa Pierre NOVEL TETRAHYDROALSTONIC DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS
BE881050A (en) * 1980-01-09 1980-07-09 Omnichemue NOVEL OXAYOHIMBANE-TYPE DERIVATIVES, PROCESS FOR OBTAINING SAME AND MEDICAMENTS CONTAINING THEM
FR2539416B1 (en) * 1983-01-14 1985-09-27 Adir NOVEL OXINDOLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
SE501156C2 (en) * 1993-04-21 1994-11-28 Ellemtel Utvecklings Ab Reference signal composed of clock signal and synchronization signal, synchronization device and method, etc. reference signal

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DE1225652B (en) * 1961-08-01 1966-09-29 Boehringer & Soehne Gmbh Process for the preparation of 3, 4, 5, 6-tetrahydroserpentine derivatives substituted in the 1-position and their salts

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DK149279A (en) 1979-10-15
ES479540A1 (en) 1979-07-16
NL7902958A (en) 1979-10-16
GB2018751A (en) 1979-10-24
PT69487A (en) 1979-05-01
FR2450835B2 (en) 1982-11-19
FI791194A (en) 1979-10-15
IT1111923B (en) 1986-01-13
LU81145A1 (en) 1980-12-16
JPS54145700A (en) 1979-11-14
IT7921793A0 (en) 1979-04-11
DE2914805A1 (en) 1979-10-18
FR2450835A2 (en) 1980-10-03
IL57061A0 (en) 1979-07-25
GR66991B (en) 1981-05-18

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