NO153890B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS Download PDF

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NO153890B
NO153890B NO813577A NO813577A NO153890B NO 153890 B NO153890 B NO 153890B NO 813577 A NO813577 A NO 813577A NO 813577 A NO813577 A NO 813577A NO 153890 B NO153890 B NO 153890B
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compound
radical
mol
alkyl
water
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NO813577A
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Norwegian (no)
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NO813577L (en
NO153890C (en
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Roland Schneider
Christian Warolin
Dennis Bigg
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Synthelabo
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Priority to DK469381A priority Critical patent/DK157853C/en
Priority to FI813330A priority patent/FI77850C/en
Priority to ZA817373A priority patent/ZA817373B/en
Priority to PT73875A priority patent/PT73875B/en
Priority to GR66337A priority patent/GR75364B/el
Priority to CA000388595A priority patent/CA1173039A/en
Priority to AU76769/81A priority patent/AU545739B2/en
Priority to IE2500/81A priority patent/IE51707B1/en
Priority to JP56170536A priority patent/JPS5872565A/en
Priority to NZ198748A priority patent/NZ198748A/en
Priority to ES506500A priority patent/ES506500A0/en
Priority to NO813577A priority patent/NO153890C/en
Publication of NO813577L publication Critical patent/NO813577L/en
Publication of NO153890B publication Critical patent/NO153890B/en
Publication of NO153890C publication Critical patent/NO153890C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Description

Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive piperidinderivater med formel (I) The present invention relates to an analogue method for the production of therapeutically active piperidine derivatives of formula (I)

hvori in which

R representerer hydrogen, C14 alkyl, hydroksy C^_4 alkyl, R represents hydrogen, C14 alkyl, hydroxy C^_4 alkyl,

C^_4 alkoksykarbonyl, fenetyl, 3-fenyl-propyl eller benzyl C 1-4 alkoxycarbonyl, phenethyl, 3-phenyl-propyl or benzyl

som kan bære en substiuent valgt fra halogen og alkoksy Cl-4' X står for en til tre substituenter som er hydrogen- which can carry a substituent selected from halogen and alkoxy Cl-4' X stands for one to three substituents which are hydrogen-

atomer eller halogenatomer eller 4 alkyl, C^_4 alkoksy, trifluormetyl, metylendioksy, eller X danner sammen med fenylkjernen en naftylgruppe, idet R og X ikke samtidig kan være hydrogenatomer, såvel som deres addisjonssalter med farmasøy- atoms or halogen atoms or 4 alkyl, C1-4 alkoxy, trifluoromethyl, methylenedioxy, or X together with the phenyl nucleus form a naphthyl group, since R and X cannot simultaneously be hydrogen atoms, as well as their addition salts with pharmaceutical

tisk tålbare syrer, og det særegne ved fremgangsmåten i hen- tically tolerable acids, and the peculiarity of the procedure in

hold til oppfinnelsen er som angitt i patentkravet. hold to the invention is as stated in the patent claim.

De forbindelser som foretrekkes er dem hvori X representerer The preferred compounds are those in which X represents

en eller flere kloratomer, eller sammen med fenylkjernen danner en naftylgruppe eller også representerer tre metoksy- one or more chlorine atoms, or together with the phenyl nucleus forms a naphthyl group or also represents three methoxy

grupper. groups.

De forbindelser hvori R er H, er av spesiell interesse. The compounds in which R is H are of particular interest.

De følgende eksempler illustrerer oppfinnelsen og analyser, og spektra (IR og NMR) bekrefter strukturen av forbindelsene. The following examples illustrate the invention and analyses, and the spectra (IR and NMR) confirm the structure of the compounds.

EKSEMPEL 1: EXAMPLE 1:

4-( 4- fluorbenzyloksy)- piperidin og dets mandelat 1. 1 1-( 4- nitrobenzoyl)- 4-( 4- fluorbenzyloksy)- piperidin. En blanding ay 1,6 g 50 % NaOH-oppløsning, 10 ml diklormetan, 2 g (0,008 mol) 1-(4-nitrobenzoyl)-4-hydroksypiperidin, 2,32 g (0,012 mol) 4-fluorbenzylbromid og 0,15 g (4 x 10~<4 >mol) tetrabutyl-ammoniumiodid omrøres i fem timer ved 50°C. Etter fortynning av reaksjonsblandingen med 20 ml vann og 30 ml diklormetan, avhelles den organiske fase, vaskes med vann til nøytral reaksjon, tørkes (MgSO^) og inndampes under vakuum. 4-(4-fluorobenzyloxy)-piperidine and its mandelate 1. 1 1-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)-piperidine. A mixture of 1.6 g of 50% NaOH solution, 10 ml of dichloromethane, 2 g (0.008 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 2.32 g (0.012 mol) of 4-fluorobenzyl bromide and 0.15 g (4 x 10~<4 >mol) of tetrabutylammonium iodide is stirred for five hours at 50°C. After diluting the reaction mixture with 20 ml of water and 30 ml of dichloromethane, the organic phase is decanted, washed with water until the reaction is neutral, dried (MgSO 4 ) and evaporated under vacuum.

Den oppnådde resterende olje krystalliseres under omrøring i eter. Det oppnås 2,23 g av et produkt som renses ved opp-løsning i 11 ml dimetylformamid (DMF) og utfelles på nytt ved dråpevis tilsetning av 11 ml vann under omrøring. Etter vasking med vanrt og tørking under vakuum oppnås 1-(4-nitro-benzoyl ) -4- ( 4-f luorbenzyloksy ) -piperidin med smeltepunkt 120°C. The residual oil obtained is crystallized while stirring in ether. 2.23 g of a product is obtained which is purified by dissolving in 11 ml of dimethylformamide (DMF) and precipitated again by the dropwise addition of 11 ml of water while stirring. After washing with water and drying under vacuum, 1-(4-nitro-benzoyl)-4-(4-fluorobenzyloxy)-piperidine is obtained with a melting point of 120°C.

1. 2 4-( 4- fluorbenzyloksy)- piperidin ( mandelat). 1. 2 4-(4-fluorobenzyloxy)-piperidine (mandelate).

En blanding av 11,48 g (0,032 mol) av produktet oppnådd under 1.1, videre 192 ml etanol og 48 ml 10 M vandig KOH-løsning omrøres under nitrogen og holdes ved 50°C i fire timer. Alkoholen avdrives under vakuum og resten opptas i 200 ml vann, 72 g natriumklorid og 200 ml eter. Etter filtrering ekstraheres den vandige fase to ganger med 200 ml eter, den totale organiske fase tørkes (MgSO^) og inndampes under vakuum. A mixture of 11.48 g (0.032 mol) of the product obtained under 1.1, further 192 ml of ethanol and 48 ml of 10 M aqueous KOH solution is stirred under nitrogen and kept at 50°C for four hours. The alcohol is driven off under vacuum and the residue is taken up in 200 ml of water, 72 g of sodium chloride and 200 ml of ether. After filtration, the aqueous phase is extracted twice with 200 ml of ether, the total organic phase is dried (MgSO 4 ) and evaporated under vacuum.

Det oppnås en olje som omdannes til d,l-mandelat ved oppløs-ning i 100 ml eter og tilsetning av 4,57 g (0,03 mol) d,l-mandelsyre. Det oppnådde salt filtreres og omkrystalliseres fra isopropanol, smeltepunkt 146°C. An oil is obtained which is converted to d,l-mandelate by dissolving in 100 ml of ether and adding 4.57 g (0.03 mol) of d,l-mandelic acid. The salt obtained is filtered and recrystallized from isopropanol, melting point 146°C.

EKSEMPEL 2: 4-( 3, 4, 5- trimetoksy- benzyloksy)- piperidin og EXAMPLE 2: 4-(3,4,5-trimethoxy-benzyloxy)-piperidine and

dets mandelat. its mandelat.

2. 1 1-( 4- nitrobenzoyl)- 4-( 3, 4, 5- trimetoksybenzyloksy)-piperidin. 2. 1 1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine.

En blanding av 0,8 g 50 % vandig NaOH-løsning, 5 ml diklormetan, 1 g (0,004 mol) 1-(4-nitrobenzoyl)-4-hydroksypiperidin, 1,30 g (0,006 mol) 3,4,5-trimetoksybenzyl og 0,08 g A mixture of 0.8 g of 50% aqueous NaOH solution, 5 mL of dichloromethane, 1 g (0.004 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 1.30 g (0.006 mol) of 3,4,5- trimethoxybenzyl and 0.08 g

-4 -4

(2 x 10 mol) tetrabutyl-ammoniumiodid omrøres i fem timer ved 50°C. Etter fortynning med 100 ml vann og 15 ml diklormetan dekanteres den organiske fase, vaskes med vann til nøy-tral reaksjon, tørkes (MgSO^) og inndampes under vakuum. (2 x 10 mol) tetrabutylammonium iodide is stirred for five hours at 50°C. After dilution with 100 ml of water and 15 ml of dichloromethane, the organic phase is decanted, washed with water until the reaction is neutral, dried (MgSO 4 ) and evaporated under vacuum.

Den oppnådde resterende olje krystalliseres ved omrøring i eter. Det oppnås 1,36 g (79 %) av et produkt som renses ved oppløsning i 7 ml DMF og sakte fornyet utfelling med 7 ml vann. Etter vasking med vann og tørking under vakuum oppnås 1-(4-nitrobenzoyl)-4-(3,4,5-trimetoksybenzyloksy)-piperidin med smeltepunkt 124°C. The residual oil obtained is crystallized by stirring in ether. 1.36 g (79%) of a product is obtained which is purified by dissolution in 7 ml of DMF and slowly renewed precipitation with 7 ml of water. After washing with water and drying under vacuum, 1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine is obtained with a melting point of 124°C.

2. 2 4-( 3, 4, 5- trimetoksybenzyloksy)- piperidin ( mandelat). 2. 2 4-(3, 4, 5-trimethoxybenzyloxy)-piperidine (mandelate).

En blanding av 12 g (0,028 mol) av produktet oppnådd under 2.1, 168 ml etanol og 48 ml vandig 10 M KOH^løsning omrøres under nitrogen og holdes ved 50°C i fire timer. Alkoholen avdrives under vakuum, resten opptas i 70 ml vann, 25,2 g natriumklorid og 70 ml kloroform. Etter filtrering ekstraheres den vandige fase to ganger med 70 ml kloroform, den totale organiske fase tørkes (MgSO^) og inndampes under vakuum. Det oppnås et pastaformet stoff som omdannes til d,l-mandelat ved oppløsning i 120 ml metanol, tilsetning av 4,26 g (0,028 mol) d,1-mandelsyre og filtrering etter omrøring av blandingen over natten ved romtemperatur. Det oppnådde bunnfall omkrystalliseres fra metanol. Produktet krystalliserer med et halvt molekyl vann og har smeltepunkt 114°C. A mixture of 12 g (0.028 mol) of the product obtained under 2.1, 168 ml of ethanol and 48 ml of aqueous 10 M KOH solution is stirred under nitrogen and kept at 50°C for four hours. The alcohol is driven off under vacuum, the residue is taken up in 70 ml of water, 25.2 g of sodium chloride and 70 ml of chloroform. After filtration, the aqueous phase is extracted twice with 70 ml of chloroform, the total organic phase is dried (MgSO 4 ) and evaporated under vacuum. A pasty substance is obtained which is converted to d,l-mandelate by dissolving in 120 ml of methanol, adding 4.26 g (0.028 mol) of d,1-mandelic acid and filtering after stirring the mixture overnight at room temperature. The precipitate obtained is recrystallized from methanol. The product crystallizes with half a molecule of water and has a melting point of 114°C.

EKSEMPEL 3: l-etoksykarbonyl-4-benzyloksy-piperidin. EXAMPLE 3: 1-ethoxycarbonyl-4-benzyloxy-piperidine.

Til en omrørt blanding av 6,83 g (0,03 mol) av hydrokloridet av 4-benzyloksy-piperidin, 7,74 g (0,056 mol) tørt I<2C03, 26 ml vann og 26 ml kloroform, tilsettes dråpevis 3,4 g (0,33 mol) etylklorformiat. Etter en times omrøring dekanteres den organiske fase etter fortynning med 54 ml kloroform, og vaskes tre ganger med 20 ml vann, tørkes (MgS04), og avdamping av løsningsmiddelet under vakuum tillater oppnåelse av en væske som destilleres under vakuum. To a stirred mixture of 6.83 g (0.03 mol) of the hydrochloride of 4-benzyloxy-piperidine, 7.74 g (0.056 mol) of dry I<2CO 3 , 26 ml of water and 26 ml of chloroform, is added dropwise 3.4 g (0.33 mol) of ethyl chloroformate. After stirring for one hour, the organic phase is decanted after dilution with 54 ml of chloroform, and washed three times with 20 ml of water, dried (MgSO 4 ), and evaporation of the solvent under vacuum allows obtaining a liquid which is distilled under vacuum.

EKSEMPEL 4: l- metyl- 4-( 4- klorbenzyloksy)- piperidin og dets EXAMPLE 4: 1-methyl-4-(4-chlorobenzyloxy)-piperidine and its

hydroklorid. hydrochloride.

I en 500 ml trehalskolbe anbragt under argonatmosfære vaskes 4,4 g (0,1 mol) natriumhydrid 55 % i olje tre ganger med petroleter. In a 500 ml three-necked flask placed under an argon atmosphere, 4.4 g (0.1 mol) sodium hydride 55% in oil is washed three times with petroleum ether.

Det tilsettes deretter 10,1 g (0,1 mol) en metyl-4-hydroksypiperidin i oppløsning 100 ml DMF. 10.1 g (0.1 mol) of a methyl-4-hydroxypiperidine in solution in 100 ml of DMF are then added.

Det omrøres i en time ved vanlig temperatur hvoretter det avkjøles med et isblandet vannbad og tilsettes 19,3 g (0,12 mol) p-klor-benzylklorid i oppløsning i 50 ml DMF. Etter avsluttet tilførsel omrøres fire timer ved romtemperatur og blandingen settes bort over natten. Reaksjonsblandingen helles ut i isblandet vann og ekstraheres tre ganger med eter. Den organiske fase vaskes en gang med vann hvoretter den ekstraheres med fortynnet HC1 (1-2 N). Den vandige fase gjøres deretter alkalisk med NaOH. Det ekstraheres med eter og vaskes fire ganger med vann. Det tørkes over magnesium-sulfat, filtreres og inndampes. Den oppnådde olje destilleres to ganger og man tar vare på den fraksjon som går over ved 94 til 98°C/0,04 mmHG. Det oppnås en olje som opptas i eter, og hydrokloridet renses med eter. Det opptas i minst mulig mengde varm isopropanol og deretter tilsettes det fem-dobbelte volum etylacetat og forbindelsen bringes til krystal- It is stirred for one hour at ordinary temperature, after which it is cooled with an ice-mixed water bath and 19.3 g (0.12 mol) of p-chlorobenzyl chloride in solution in 50 ml of DMF are added. After completion of the addition, the mixture is stirred for four hours at room temperature and the mixture is set aside overnight. The reaction mixture is poured into ice-cold water and extracted three times with ether. The organic phase is washed once with water after which it is extracted with dilute HCl (1-2 N). The aqueous phase is then made alkaline with NaOH. It is extracted with ether and washed four times with water. It is dried over magnesium sulphate, filtered and evaporated. The oil obtained is distilled twice and the fraction that passes over at 94 to 98°C/0.04 mmHG is kept. An oil is obtained which is taken up in ether, and the hydrochloride is purified with ether. It is taken up in the smallest possible amount of warm isopropanol and then the five-fold volume of ethyl acetate is added and the compound is brought to crystal

lisasjon. Smeltepunkt 149 til 151°C. lization. Melting point 149 to 151°C.

EKSEMPEL 5: l- benzyl- 4-( 3, 4, 5- trimetoksybenzyloksy)-piperidin og dets fumarat. EXAMPLE 5: 1-benzyl-4-(3,4,5-trimethoxybenzyloxy)-piperidine and its fumarate.

I en 250 ml trehalskolbe anbragt under nitrogenatmosfære vaskes 2,2 g (0,05 mol) natriumhydrid 55 % i olje tre ganger med petroleter. Det innføres deretter 9,6 g (0,05 mol) l-benzyl-4-hydroksypiperidin i oppløsning i 30 ml DMF. Etter avsluttet tilsetning omrøres i en time ved romtemperatur. In a 250 ml three-necked flask placed under a nitrogen atmosphere, 2.2 g (0.05 mol) of sodium hydride 55% in oil are washed three times with petroleum ether. 9.6 g (0.05 mol) of 1-benzyl-4-hydroxypiperidine in solution in 30 ml of DMF are then introduced. After the addition is complete, stir for one hour at room temperature.

Man tilsetter deretter under avkjøling med et isblandet vannbad 13 g (0,06 mol) 3,4,5-trimetoksybenzylklorid i 30 ml DMF. Det omrøres i fem timer ved vanlig temperatur hvoretter blandingen settes bort over natten. 13 g (0.06 mol) of 3,4,5-trimethoxybenzyl chloride in 30 ml of DMF are then added while cooling with an ice-mixed water bath. It is stirred for five hours at normal temperature, after which the mixture is set aside overnight.

Reaksjonsblandingen uttelles i isblandet vann og ekstraheres med eter. Produktet ekstraheres deretter med fortynnet HC1. Den vandige fase gjøres alkalisk med NaOH hvoretter den ekstraheres med eter, vaskes med vann, tørkes over MgSO^, filtreres og.inndampes. Den oppnådde olje opptas i varm pentan. Produktet krystalliseres, filtreres og omkrystalliseres fra isopropanol. Man oppnår basen som oppløses i 70 ml etanol og det tilsettes en filtrert oppløsning av 2,9 g (0,025 mol) fumarsyre i 140 ml etanol. Det filtreres og det dannede salt tørkes. Smeltepunkt er lik 160-161°C. The reaction mixture is poured into ice-cold water and extracted with ether. The product is then extracted with dilute HCl. The aqueous phase is made alkaline with NaOH, after which it is extracted with ether, washed with water, dried over MgSO 4 , filtered and evaporated. The oil obtained is taken up in hot pentane. The product is crystallized, filtered and recrystallized from isopropanol. The base is obtained which is dissolved in 70 ml of ethanol and a filtered solution of 2.9 g (0.025 mol) of fumaric acid in 140 ml of ethanol is added. It is filtered and the formed salt is dried. Melting point is equal to 160-161°C.

EKSEMPEL 6: 1-( 4- klorbenzyl)- 4-( 3, 4, 5- trimetoksybenzyloksy)-piperidin og dets fumarat. EXAMPLE 6: 1-(4-chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine and its fumarate.

6. 1 - 1-( 4- klorbenzoyl)- 4- hydroksy- piperidin. 6. 1 - 1-(4-chlorobenzoyl)-4-hydroxypiperidine.

I en 1 liters erlenmeyerkolbe anbringes 30 g (0,296 mol) 4-hydroksypiperidin, 260 ml CHC13, 57,3 g (0,414 mol) In a 1 liter Erlenmeyer flask, place 30 g (0.296 mol) 4-hydroxypiperidine, 260 ml CHCl 3 , 57.3 g (0.414 mol)

K^ CO^ og 260 ml vann. K^ CO^ and 260 ml of water.

Det tilsettes i løpet av 15 minutter under avkjøling med et isblandet vannbad 51,8 g (0,296 mol) p-klor-benzoylklorid opp-løst i 50 ml CHCl^. Det omrøres over natten ved vanlig temperatur, dekanteres, ekstraheres med CHCl^ og vaskes med vann til pH 6-7. Det tørkes over MgSO^, filtreres og inndampes. Blandingen omkrystalliseres fra etylacetat. 6. 2 - 1-( 4- klorbenzoyl)- 4-( 3, 4, 5- trimetoksybenzyloksy)-piperidin. 51.8 g (0.296 mol) of p-chloro-benzoyl chloride dissolved in 50 ml of CHCl 2 are added over 15 minutes while cooling with an ice-mixed water bath. It is stirred overnight at ordinary temperature, decanted, extracted with CHCl^ and washed with water to pH 6-7. It is dried over MgSO^, filtered and evaporated. The mixture is recrystallized from ethyl acetate. 6. 2-1-(4-chlorobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine.

I en trehalskolbe under nitrogenatmosfære vaskes 0,96 g (0,022 mol) NaH 55 % i olje tre ganger med petroleter. In a three-necked flask under a nitrogen atmosphere, 0.96 g (0.022 mol) of NaH 55% in oil are washed three times with petroleum ether.

Det tilsettes deretter 4,8 g (0,02 mol) av forbindelsen oppnådd under 6.1 oppløst i 50 ml DMF. Det omrøres i en time etter avsluttet tilsetning ved vanlig temperatur. Det av-kjøles deretter med et isblandet vannbad og tilsettes 5,4 g (0,025 mol) 3,4,5-trimetoksymetylklorid oppløst i 10 ml DMF. Det omrøres i tre timer ved vanlig temperatur hvoretter blandingen settes bort over natten. 4.8 g (0.02 mol) of the compound obtained under 6.1 dissolved in 50 ml of DMF are then added. It is stirred for one hour after the addition has been completed at normal temperature. It is then cooled with an ice-mixed water bath and 5.4 g (0.025 mol) of 3,4,5-trimethoxymethyl chloride dissolved in 10 ml of DMF are added. It is stirred for three hours at normal temperature, after which the mixture is set aside overnight.

Blandingen helles ut i isblandet vann og ekstraheres med etylacetat. The mixture is poured into ice-cold water and extracted with ethyl acetate.

Det vaskes med vann, tørkes over MgSO^, filtreres og inndampes. Den oppnådde olje opptas i eter og filtreres. Fil-tratet inndampes og føres.gjennom en kolonne med aluminium-oksyd (elueringsmiddel CHCl^). Produktet krystalliserer ikke og anvendes som sådant i det etterfølgende trinn. It is washed with water, dried over MgSO^, filtered and evaporated. The oil obtained is taken up in ether and filtered. The filtrate is evaporated and passed through a column with aluminum oxide (eluent CHCl3). The product does not crystallize and is used as such in the subsequent step.

6- 3 - 1-( 4- klorbenzyl)- 4-( 3, 4, 5- trimetoksybenzyloksy)-piperidin og dets fumarat. 6-3-1-(4-chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine and its fumarate.

I en kolbe under nitrogenatmosfære innføres ved vanlig temperatur til en suspensjon av 0,38 g (0,01 mol), AlLiH^ i 30 ml tørr eter, 7 g (0,0167 mol) av forbindelsen oppnådd under 6.2, oppløst i 70 ml tørr eter. Det oppvarmes i tre timer ved tilbakeløpstemperaturen. Det hydrolyseres med 2,6 ml isopropanol og 3,3 ml vann mettet med NaCl. Det filtreres og renses med eter. Produktet ekstraheres med fortynnet saltsyre og deretter gjøres reaksjonsblandingen alkalisk med NH^OH og ekstraheres med eter. Man vasker med vann, tørker over MgS04, filtrerer og inndamper. Det oppnås en olje som oppløses i 30 ml etanol og tilsettes til en filtrert oppløsning av 1,2 g (0,0105 mol) fumarsyre i 60 ml etanol. Fumaratet faller sakte ut. Det filtreres, renses med litt etanol og deretter med eter og tørkes. Smeltepunkt er 178-180°C. Into a flask under a nitrogen atmosphere, introduce at room temperature to a suspension of 0.38 g (0.01 mol), AlLiH^ in 30 ml of dry ether, 7 g (0.0167 mol) of the compound obtained under 6.2, dissolved in 70 ml dry ether. It is heated for three hours at the reflux temperature. It is hydrolysed with 2.6 ml of isopropanol and 3.3 ml of water saturated with NaCl. It is filtered and purified with ether. The product is extracted with dilute hydrochloric acid and then the reaction mixture is made alkaline with NH^OH and extracted with ether. Wash with water, dry over MgSO4, filter and evaporate. An oil is obtained which is dissolved in 30 ml of ethanol and added to a filtered solution of 1.2 g (0.0105 mol) of fumaric acid in 60 ml of ethanol. The fumarate precipitates slowly. It is filtered, cleaned with a little ethanol and then with ether and dried. Melting point is 178-180°C.

Forbindelser fremstilt i samsvar med de foregående eksempler representeres ved hjelp av den etterfølgende tabell,s. 9- 12. Compounds prepared in accordance with the preceding examples are represented by means of the following table, p. 9-12.

Forbindelsene (I) ble underkastet farmakologiske forsøk som viser deres antidepressive virkning. The compounds (I) were subjected to pharmacological tests showing their antidepressant action.

Giftigheten av forbindelsene ble bestemt i mus, ved i.p.-tilførsel. LD 50 varierer fra 30 til 1000 mg/kg. The toxicity of the compounds was determined in mice by i.p. administration. LD 50 varies from 30 to 1000 mg/kg.

Den antidepressive virkning ble bestemt i henhold til antagon-ismetesten overfor reserpinptosis (Gouret C. et al, The antidepressant effect was determined according to the reserpineptosis antagonism test (Gouret C. et al,

J. Pharmacol (Paris 8, 333-350, 1977). J. Pharmacol (Paris 8, 333-350, 1977).

Mus, (hannmus, CDl Charles River, Frankrike, 18-22 g) mottok samtidig de produktene som skulle studeres eller løsnings-middelet (i.p.-tilførsel) og reserpin (4 mg/kg, s.c.-tilførsel) . 60 min. senere ble øyelokk-ptosis bestemt ved hjelp av en bedømmelsesskala (0,4) for hver mus. Mice, (male mice, CD1 Charles River, France, 18-22 g) simultaneously received the products to be studied or the solvent (i.p. administration) and reserpine (4 mg/kg, s.c. administration). 60 min. later, eyelid ptosis was determined using a rating scale (0.4) for each mouse.

Ved hver dose ble den midlere bedømmelse bg prosentvise variasjon i forhold til kontrolldyrene beregnet. At each dose, the mean assessment bg percentage variation in relation to the control animals was calculated.

For hvert produkt ble AD 50, eller den dose som nedsetter den midlere verdi av ptosis i forhold til kontrolldyrene med 50 %, bestemt grafisk. For each product, the AD 50, or the dose which reduces the mean value of ptosis in relation to the control animals by 50%, was determined graphically.

AD 50 varierer fra 4 til 10 mg/kg ved i.p.-tilførsel. AD 50 varies from 4 to 10 mg/kg by i.p. administration.

Den antidepressive aktivitet ble likeledes bestemt i henhold til potensialiseringstesten ved hodevridninger frembragt med L-5-hydroksytryptofan (Van Riezen, H. (1972) Arch. Int. Pharmacology, 198, 256.269). 24 timer før forsøket anbringes dyrene i laboratoriet hvor de skal behandles. Forsøksdagen ble musene veiet og bedøvet. The antidepressant activity was likewise determined according to the potentiation test by head twists produced with L-5-hydroxytryptophan (Van Riezen, H. (1972) Arch. Int. Pharmacology, 198, 256,269). 24 hours before the experiment, the animals are placed in the laboratory where they will be treated. On the day of the experiment, the mice were weighed and anesthetized.

Deretter ble testproduktene injisert med i.p.-tilførsel før injeksjon av L5-HTP ved s.c.-tilførsel med 125 mg/kg i suspensjon i "Tween". Man teller antallet "hodevridninger" Then the test products were injected by i.p. administration before injection of L5-HTP by s.c. administration at 125 mg/kg in suspension in "Tween". One counts the number of "head twists"

30 min. etter injeksjon av L5-HTP i løpet av 60 sek. 30 min. after injection of L5-HTP within 60 sec.

For hver dose beregnes middeltallet av hodevridninger og den prosentvise variasjon i forhold til blindprøver. Aktiv dose 50 etableres ved hjelp av en grafisk kurve. For each dose, the mean number of head twists and the percentage variation compared to blank samples are calculated. Active dose 50 is established using a graphic curve.

AD 50 varierer fra 0,1 til 5 mg/kg ved i.p.-tilførsel. The AD 50 varies from 0.1 to 5 mg/kg by i.p. administration.

De farmakologiske resultater viser at forbindelsene kan anvendes ved behandling av depresjoner. The pharmacological results show that the compounds can be used in the treatment of depression.

Forbindelsene kan tilføres i enhver form passende for oral eller parenteral tilførsel, for eksempel i form av tabletter, drasjeer, geler, drikkbare eller injiserbare oppløsninger, etc, i forbindelse med vanlige tilsetningsmidler. The compounds can be supplied in any form suitable for oral or parenteral administration, for example in the form of tablets, dragees, gels, drinkable or injectable solutions, etc., in conjunction with common additives.

Det ble for ytterligere utprøvning av de ved fremgangsmåten fremstillbare forbindelser foretatt sammenligning med en meget nærliggende forbindelse, nemlig 4-benzyloksy-piperidin, i det følgende betegnet som sammenligningsforbindelse. For further testing of the compounds that can be prepared by the method, a comparison was made with a very similar compound, namely 4-benzyloxy-piperidine, hereinafter referred to as the comparison compound.

Ved denne sammenligning ble forbindelsene med nummere oppført i tabellen som 3, 5, 6, 13, 17, 21, 23, 24, 25, 26, 27, 28, 29, 31, 34, 35, 40, 41,.46, 48, 47 og 49 sammenlignet med sammenligningsforbindelsen. Testforbindelsene hadde sammen-lignbar . renhet med 4-benzyloksy-piperidin-hydrokloridet. Resultatene av forsøkene er gjengitt i den etterfølgende tabell. In this comparison, the compounds with numbers listed in the table as 3, 5, 6, 13, 17, 21, 23, 24, 25, 26, 27, 28, 29, 31, 34, 35, 40, 41,.46, 48, 47 and 49 compared to the comparison compound. The test compounds had comparable . purity with the 4-benzyloxy-piperidine hydrochloride. The results of the experiments are reproduced in the following table.

Sammenligningsforbindelsen var fremstilt ved hjelp av syntesen beskrevet i europeisk patentansøkning 15.817 og hadde en høy renhetsgrad egnet for sammenligning ved standard.farmasøy-tiske tester. The comparison compound was prepared using the synthesis described in European patent application 15,817 and had a high degree of purity suitable for comparison in standard pharmaceutical tests.

Forsøkene ble gjennomført i samsvar med metoden angitt i det foregående, d.v.s. at den antidepressive virkning ble bestemt ved hjelp av potensieringstesten for hodevridninger indusert ved L-5-hydroksytryptofan og tabellen gir resultatene i form av ED50 for hver forbindelse, d.v.s. den effektive dose som øker hodevridningene med 50 % i forhold til kontrollmus. Tabellen viser også akutt giftighet (LD50) av de testede forbindelser såvel som forholdet LD50/ED50. The experiments were carried out in accordance with the method stated above, i.e. that the antidepressant effect was determined using the potentiation test for head twists induced by L-5-hydroxytryptophan and the table gives the results in terms of ED50 for each compound, i.e. the effective dose that increases head twists by 50% compared to control mice. The table also shows the acute toxicity (LD50) of the tested compounds as well as the ratio LD50/ED50.

Av den nevnte tabell fremgår tydelig at 4-benzyloksy-piperidin It is clear from the aforementioned table that 4-benzyloxy-piperidine

-hydroklorid, i tabellen oppført som sammenligningsforbindelse, ikke er brukbar som et antidepressivt middel ved den maksimale testdose på 10 mg/kg, i motsetning til aktiviteten i disse nivåer for de testede forbindelser som kan fremstilles i henhold til oppfinnelsen. -hydrochloride, in the table listed as a comparison compound, is not usable as an antidepressant at the maximum test dose of 10 mg/kg, in contrast to the activity at these levels for the tested compounds that can be prepared according to the invention.

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive piperidinderivater med formel (I) hvori R står for hydrogen, C^_4 alkyl, hydroksy C^_4 alkyl, C1_4 alkoksykarbonyl, fenetyl, 3-fenyl-propyl, eller benzyl som kan bære en substituent valgt fra halogen og alkoksy<C>l-4' X står for en til tre substituenter som er hydrogenatomer eller halogenatomer eller C^_4 alkyl, C^_4 alkoksy, tri- fluormetyl, metylendioksy eller X danner sammen med fenyl- kjernen en naftylgruppe, idet R og X ikke samtidig representerer hydrogenatomer, såvel som deres addisjonssalter med farmasøytisk tålbare syrer,karakterisert ved at en forbindelse (II) hvori R' representer en nitrogenbeskyttende gruppe som 4-nitro- benzoyl, eventuelt substituert benzoyl, eventuelt substituert benzyl eller alkyl, omsettes med en forbindelse (III)Analogous process for the preparation of therapeutically active piperidine derivatives of formula (I) in which R stands for hydrogen, C₁₄ alkyl, hydroxy C₄₄ alkyl, C₁₄₄ alkoxycarbonyl, phenethyl, 3-phenyl-propyl, or benzyl which may carry a substituent selected from halogen and Alkoxy<C>1-4' X stands for one to three substituents which are hydrogen atoms or halogen atoms or C^_4 alkyl, C^_4 alkoxy, trifluoromethyl, methylenedioxy or X forms together with the phenyl nucleus a naphthyl group, where R and X does not at the same time represent hydrogen atoms, as well as their addition salts with pharmaceutically acceptable acids, characterized in that a compound (II) in which R' represents a nitrogen-protecting group such as 4-nitrobenzoyl, optionally substituted benzoyl, optionally substituted benzyl or alkyl, is reacted with a compound (III) hvoriin which Y representerer et reaktivt radikal som et kloratom eller bromatom, hvoretter det beskyttende radikal r' f jernes hvis det ikke tilsvarer et radikal R med den ovennevnte betydning, eller det eventuelt substituerte benzoylradikal reduseres, eller en forbindelse (I)Y represents a reactive radical such as a chlorine atom or bromine atom, after which the protective radical r' is removed if it does not correspond to a radical R with the above meaning, or the optionally substituted benzoyl radical is reduced, or a compound (I) hvori X har den ovennevnte betydning, omsettes med en forbindelse RZ hvori R har den ovennevnte betydning og Z er en reaktiv gruppe som kan innføre radikalet R og, om ønsket, omdannes forbindelsen I i form av den fri base til syre-addisjonssalter med farmasøytisk tålbare syrer.in which X has the above meaning, is reacted with a compound RZ in which R has the above meaning and Z is a reactive group which can introduce the radical R and, if desired, the compound I is converted in the form of the free base into acid addition salts with pharmaceutically acceptable acids.
NO813577A 1981-10-23 1981-10-23 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS. NO153890C (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
DK469381A DK157853C (en) 1981-10-23 1981-10-23 ANALOGY PROCEDURE FOR THE PREPARATION OF 4-BENZYLOXYPIPERIDE INGREDIATES
FI813330A FI77850C (en) 1981-10-23 1981-10-23 Process for the preparation of 4-benzyloxy or 4-naphthylmethoxypipe ridin derivatives which have antidepressant effect.
ZA817373A ZA817373B (en) 1981-10-23 1981-10-23 Piperidine derivatives,their preparation and pharmaceutical compositions containing them
PT73875A PT73875B (en) 1981-10-23 1981-10-23 PROCESS FOR THE PREPARATION OF THERAPEUTICALLY APPLICABLE PIPERIDINE DERIVATIVES
GR66337A GR75364B (en) 1981-10-23 1981-10-23
CA000388595A CA1173039A (en) 1981-10-23 1981-10-23 4-benzyloxypiperidine compounds
AU76769/81A AU545739B2 (en) 1981-10-23 1981-10-23 Piperidine derivatives
IE2500/81A IE51707B1 (en) 1981-10-23 1981-10-23 Piperidine derivatives,their preparation and pharmaceutical compositions containing them
JP56170536A JPS5872565A (en) 1981-10-23 1981-10-23 Piperidine derivative and application to medicine
NZ198748A NZ198748A (en) 1981-10-23 1981-10-23 Piperidine derivatives and pharmaceutical compositions
ES506500A ES506500A0 (en) 1981-10-23 1981-10-23 PIPERIDINE DERIVATIVES PREPARATION PROCEDURE
NO813577A NO153890C (en) 1981-10-23 1981-10-23 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS.

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
DK469381A DK157853C (en) 1981-10-23 1981-10-23 ANALOGY PROCEDURE FOR THE PREPARATION OF 4-BENZYLOXYPIPERIDE INGREDIATES
FI813330A FI77850C (en) 1981-10-23 1981-10-23 Process for the preparation of 4-benzyloxy or 4-naphthylmethoxypipe ridin derivatives which have antidepressant effect.
ZA817373A ZA817373B (en) 1981-10-23 1981-10-23 Piperidine derivatives,their preparation and pharmaceutical compositions containing them
PT73875A PT73875B (en) 1981-10-23 1981-10-23 PROCESS FOR THE PREPARATION OF THERAPEUTICALLY APPLICABLE PIPERIDINE DERIVATIVES
GR66337A GR75364B (en) 1981-10-23 1981-10-23
CA000388595A CA1173039A (en) 1981-10-23 1981-10-23 4-benzyloxypiperidine compounds
AU76769/81A AU545739B2 (en) 1981-10-23 1981-10-23 Piperidine derivatives
IE2500/81A IE51707B1 (en) 1981-10-23 1981-10-23 Piperidine derivatives,their preparation and pharmaceutical compositions containing them
JP56170536A JPS5872565A (en) 1981-10-23 1981-10-23 Piperidine derivative and application to medicine
NZ198748A NZ198748A (en) 1981-10-23 1981-10-23 Piperidine derivatives and pharmaceutical compositions
ES506500A ES506500A0 (en) 1981-10-23 1981-10-23 PIPERIDINE DERIVATIVES PREPARATION PROCEDURE
NO813577A NO153890C (en) 1981-10-23 1981-10-23 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS.

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NO813577L NO813577L (en) 1983-04-25
NO153890B true NO153890B (en) 1986-03-03
NO153890C NO153890C (en) 1986-06-11

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JP (1) JPS5872565A (en)
AU (1) AU545739B2 (en)
CA (1) CA1173039A (en)
DK (1) DK157853C (en)
ES (1) ES506500A0 (en)
FI (1) FI77850C (en)
GR (1) GR75364B (en)
IE (1) IE51707B1 (en)
NO (1) NO153890C (en)
NZ (1) NZ198748A (en)
PT (1) PT73875B (en)
ZA (1) ZA817373B (en)

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JPH02148948U (en) * 1989-05-17 1990-12-18
US5169855A (en) * 1990-03-28 1992-12-08 Du Pont Merck Pharmaceutical Company Piperidine ether derivatives as psychotropic drugs or plant fungicides
JPH0535676U (en) * 1991-06-06 1993-05-14 株式会社カネマス Pack for reconstitution of dried seaweed

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AU7676981A (en) 1983-04-28
ES8206476A1 (en) 1982-08-16
NZ198748A (en) 1984-08-24
FI813330L (en) 1983-04-24
JPS5872565A (en) 1983-04-30
DK157853C (en) 1990-08-06
IE812500L (en) 1983-04-21
JPS6135177B2 (en) 1986-08-12
ZA817373B (en) 1983-03-30
ES506500A0 (en) 1982-08-16
DK469381A (en) 1983-04-24
NO813577L (en) 1983-04-25
DK157853B (en) 1990-02-26
GR75364B (en) 1984-07-13
IE51707B1 (en) 1987-02-18
CA1173039A (en) 1984-08-21
AU545739B2 (en) 1985-08-01
FI77850C (en) 1989-05-10
NO153890C (en) 1986-06-11
PT73875B (en) 1983-01-25
FI77850B (en) 1989-01-31
PT73875A (en) 1981-11-01

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