DK153709B - Analogifremgangsmaade til fremstilling af 4-substituerede piperidinoalkanolderivater - Google Patents

Analogifremgangsmaade til fremstilling af 4-substituerede piperidinoalkanolderivater Download PDF

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DK153709B
DK153709B DK132980AA DK132980A DK153709B DK 153709 B DK153709 B DK 153709B DK 132980A A DK132980A A DK 132980AA DK 132980 A DK132980 A DK 132980A DK 153709 B DK153709 B DK 153709B
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compounds
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piperidinyl
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DK153709C (da
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Albert A Carr
Joseph E Dolfini
George J Wright
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Richardson Merrell Inc
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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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

DK 153709B
o
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 4-substitue-rede piperidinoalkanolderivater, der er anvendelige som antihistaminer, antiallergiske midler og bronchodilatorer, 5 hvilken fremgangsmåde er ejendommelig ved det i krav l's kendetegnende del angivne.
Beslægtede piperidinderivater med antihistamin-egenskaber findes beskrevet i US-patentskrifterne nr. 3.806.526, 3.829.433, 3.862.173, 3.878.217, 3.931.197, 3.941.795, 10 3.946.022 og 3.965.257.
De her omhandlede, hidtil ukendte 4-substituerede piperidinoalkanolderivater, der er anvendelige som antihistaminer, antiallergiske midler og bronchodilatorer, er forbindelser med formlen 15 99 C—OH ^ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
(V
OH CH, 2 KH2,3-CH-(3-C-r3 ch3 3
hvor J
4 3 5 R er -COOH eller -COO-alkyl, hvor alkylgruppen indeholder 6 7 1-6 carbonatomer og er ligekædet eller forgrenet, eller farmaceutisk acceptable salte af disse forbindelser.
8
De her omhandlede forbindelser med formlen (I) ud 9 viser en bedre antihistamin virkning end kendte, nært be 10 slægtede forbindelser.
11 12
Eksempler på ligekædede eller forgrenede alkylgrup- 13 per med 1-6 carbonatomer som nævnt ovenfor er methyl, ethyl, n-propyl, isopropyl, n-butyl, sek.butyl, tert.butyl, n--pentyl, neopentyl og n-hexyl.
14 3 15 Særligt foretrukne er de forbindelser, hvori R er 16 -COOH.
O
DK 153709B
2
De farmaceutisk acceptable syreadditionssalte af de fremstillede forbindelser er salte med enhver egnet u-organisk eller organisk syre. Ikke-toxiske salte af de fremstillede forbindelser med uorganiske og organiske ba-5 ser omfatter f.eks. saltene af alkalimetaller, såsom natrium, kalium og lithium, jordalkalimetallerne, f.eks. calcium og magnesium, de lette metaller af gruppen IIIA, f.eks. aluminium, samt organiske aminer såsom primære, sekundære og tertiære aminer, f.eks. cyclohexylamin, ethylamin, pyri-10 din, methylaminoethanol og piperazin. Saltene fremstilles på sædvanlig måde, f.eks. ved behandling af en forbindelse af formlen I med en passende syre eller base.
Forbindelserne af formel I er som nævnt anvendelige som antihistaminer, antiallergiske midler og bronchodila-15 torer og kan indgives alene eller sammen med passende farmaceutiske bærere i fast eller flydende form, f.eks. som tabletter, kapsler, pulvere, opløsninger, suspensioner eller emulsioner.
Den indgivne mængde kan variere over et bredt om-2o råde til tilvejebringelse i en enhedsdosis af en effektiv mængde på mellem ca. 0,01 og ca. 20 mg pr. kg legemsvægt om dagen til opnåelse af den ønskede virkning. Således kan f.eks. de ønskede virkninger opnås ved indgivning af en enhedsdosisform såsom en tablet indeholdende 1-50 mg af 25 den aktive forbindelse, taget 1-4 gange daglig.
Som eksempel på forbindelsernes anvendelighed kan nævnes, at 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]--1-hydroxybutyl]-α,α-dimethylbenzeneddikesyre i en koncen- _7 tration på 1 x 10 M giver en kendelig formindskelse af 30 histamin-fremkaldt sammentrækning af isolerede ileal- -muskler fra marsvin.
Forbindelserne af formlen I fremstilles ved en fremgangsmåde, ved hvilken den tilsvarende alkanon reduceres selektivt, hvorefter, om ønsket, en fremstillet for- 3 35 bindelse, hvori R er -COO-alkyl, omdannes til en forbm- 3 delse, hvori R er -COOH, ved base-hydrolyse, og/eller 3
DK 153709B
O
den dannede forbindelse omdannes til et farmaceutisk acceptabelt salt.deraf.
Af det følgende reaktionsskema vil det fremgå, at forbindelserne af formlen I kan fremstilles i et enkelt 5 trin ved reduktion af den tilsvarende keton eller i to trin ved reduktion af en passende keton efterfulgt af en base-hydrolyse afhængende af den ønskede forbindelse.
10 15 20 25 30 35
DK 153709B
4
REAKTIONSSKEMA I
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DK 153709B
I reaktionsskema I indeholder alkylgruppen i forbindelserne 4 og VIII 1-6 carbonatomer og er ligekædet eller forgrenet.
Reduktion af de forskellige forbindelser som vist i 5 reaktionsskema I under anvendelse af f.eks. natriumborhydrid eller kaliumborhydrid udføres i en lavere alkohol såsom methanol, ethanol, isopropylalkohol eller n-butanol. Disse reduktionsreaktioner udføres ved temperaturer fra ca. 0°C til tilbagesvalingstemperaturen for opløsningsmidlet, og 10 reaktionstiden varierer fra ca. 1/2 til ca. 8 timer.
Katalytisk reduktion kan også anvendes til fremstilling af forbindelserne af formlen I som vist i reaktionsskemaet under anvendelse af f.eks. Raney-nikkel-, palladium-, platin- eller rhodium-katalysatorer i lavere alko-15 holer såsom methanol, ethanol, isopropylalkohol eller n--butanol eller eddikesyre eller deres vandige blandinger, eller ved anvendelse af aluminiumisopropoxid i isopropylalkohol. Basisk hydrolyse af forbindelserne VIII til dannelse af forbindelserne X sker efter sædvanlige metoder, 2o f.eks. ved behandling med en uorganisk base såsom natriumeller kaliumhydroxid i en vandig lavere alkohol såsom vandig methanol, ethanol, isopropylalkohol eller n-butanol ved tilbagesvalingstemperatur i et tidsrum mellem ca. 1/2 og ca. 12 timer.
25 De keton-forbindelser, der anvendes som udgangsfor bindelser, dvs. forbindelserne 4 og 8 i reaktionsskema I fremstilles ved alkylering af et substitueret piperidin--derivat af formlen 00
Von tf
H
35 med en ω-halogenalkyl-substitueret phenylketon af formlen
O
DK 153709B
6 0 CH3 hal-(CH2)3-C-^^-C-R3 (XV) έκ3 5 i hvilke formler hal er halogen såsom chlor, brom eller 3 iod, og R er -COO-alkyl, hvor alkylgruppen indeholder 3 1-6 carbonatomer og er ligekædet eller forgrenet. Når R er -COOH, efterfølges alkyleringen af en base-hydrolyse.
10 Alkyleringen udføres i et passende opløsningsmiddel, for trinsvis i nærværelse af en base og eventuelt i nærværelse af en katalytisk mængde kaliumiodid over et tidsrum på mellem ca. 4 og ca. 120 timer og ved temperaturer mellem ca.
70°C og tilbagesvalingstemperaturen for opløsningsmidlet.
15 Eksempler på egnede opløsningsmidler til alkyleringsreak-tionen er alkoholer, f.eks. methanol, ethanol, isopropyl-alkohol og n-butanol, ketoner, f.eks. methylisobutylketon, qarbonhydrider, f.eks. benzen, toluen og xylen, og halogenerede carbonhydrider, f.eks. chlorbenzen eller methylenchlo-20 rid, samt dimethylformamid. Egnede baser til alkylerings-reaktionen omfatter uorganiske baser, f.eks. natriumbicar-bonat, kaliumcarbonat og kaliumbicarbonat, og organiske baser såsom trialkylaminer, f.eks. triethylamin, og pyri-din, men der kan også anvendes et overskud af en forbin-25 delse af formlen XIV. En base-hydrolyse af de forbindelser, 3 hvori R er -COO-alkyl, til dannelse af de tilsvarende forbindelser, hvori R er -COOH, opnås ved behandling med en uorganisk base som f.eks. natriumhydroxid i en vandig lavere alkohol såsom vandig methanol, ethanol, isopropyl-30 alkohol eller n-butanol ved tilbagesvalingstemperatur i et tidsrum mellem ca. 1/2 og ca. 12 timer.
Forbindelserne af formlen XIV kan fås i handelen. Forbindelserne af formlen XV fremstilles ved omsætning af en passende ligekædet eller forgrenet, lavere 35 alkyl-C^-Cg-ester af α,α-dimethylphenyleddikesyre, der er en kendt forbindelse eller kan fremstilles efter kendte metoder, med en forbindelse af formlen 0
O
DK 153709B
7 hal-(CH2)3-C-hal (XVII) hvori hal er som angivet ovenfor, under de generelle be-5 tingelser for en Friedel-Crafts-acylering. Denne reaktion udføres i et opløsningsmiddel såsom carbondisulfid, tetra-chlorethan eller nitrobenzen, hvoraf carbondisulfid er at foretrække. Reaktionstiden varierer fra ca. 1/2 til ca. 8, fortrinsvis fra ca. 3 til ca. 5 timer, og reaktionstempera-10 turen varierer fra ca. 0 til ca. 25°C.
Forbindelserne af formlen XVII fås i handelen eller kan fremstilles efter kendte metoder.
De følgende eksempler skal tjene til nærmere illustrering af fremgangsmåden ifølge opfindelsen.
15 EKSEMPEL 1
Ethyl-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1--hydroxybuty 13 -ex,, α-dimethylbenzenacetat-hydrochlorid
En opløsning af 5,64 g (0,01 mol) ethyl-4-[4-[4-20 -(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxohutyl]-α,α- -dimethylbenzenacetat-hydrochlorid i 200 ml absolut ethanol og 50 ml methanol og 0,5 g platinhydroxid hydrogene-res ved ca. 3,5 kg/cm i ca. 1 time, indtil IR ikke viser noget tegn på en keton-carbonylfunktion. Derefter filtre-25 res opløsningen, og filtratet inddampes, hvorefter om-krystallisation fra butanon og methanol/butanan giver ethyl-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1--hydroxybutyl]-a,a-dimethylbenzenacetat, HC1 med smp.
185-187°C.
30 EKSEMPEL 2 4-[4-[4-(Hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxy-buty1]-a,a-dimethylbenzeneddikesyre
Til en opløsning af 0,6 g ethyl-4-[4-[4-(hydroxy-35 diphenylmethyl)-1-piperidinyl]-1-hydroxybuty1]-a,a-di- methylbenzenacetat i 20 ml absolut ethanol sættes 10 ml
O
DK 153709B
8 af en 50%'s natriumhydroxidopløsning, og blandingen holdes under tilbagesvaling i 3 1/2 time, hvorefter den inddampes til et fast stof, og der tilsættes den mindst mulige mængde methanol til opløsning af remanensen. Derefter til-5 sættes 10%'s vandig HC1, indtil pH-værdien er 7, methano-len fjernes ved afdampning, og 25 ml vand tilsættes. Ved omkrystallisering af det fremkomne bundfald fra methanol/-butanon fås 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]--l-hydroxybutyl]-a,a-dimethylbenzeneddikesyre med smp.
-10 195-197°C.
EKSEMPEL 3
Fremstilling af udgangsprodukt (A) Til 700 ml carbondisulfid indeholdende 36,5 g 15 (0,254 mol) 4-chlorbutyrylchlorid sættes 74,5 g (0,56 mol) aluminiumchlorid under omrøring ved -10°C, og omrøringen fortsættes i ca. 15 minutter ved ca. 25°C, hvorpå blandingen igen afkøles til 5°C og tilsættes 48,4 g (0,294 mol) ethyl-a-dimethylphenylacetat i 100 ml carbondisulfid. Reak-20 tionsblandingen omrøres i isbad i 3 1/2 time, og derefter i 15 1/2 time ved 25°C, hvorefter den hældes ud i HC1/-isvand og ekstraheres med chloroform. Ekstrakten vaskes med fortyndet natriumcarbonat-opløsning, vand og mættet natriumchlorid-opløsning, tørres over magnesiumsulfat og 25 inddampes, hvilket giver ethyl-4-(4-chlor-l-oxobutyl)-α,α--dimethylphenylacetat som et fast stof.
(B) En blanding af 4,5 g (0,0163 mol) 4-(a,a-di-phenyl)-piperidinmethanol, 6,1 g (0,0205 mol) ethyl-4- -(4-chlor-l-oxobutyl)-a,a-dimethylphenylacetat, 5 g (0,05 30 mol) kaliumbicarbonat og 0,05 g kaliumiodid i 50 ml toluen omrøres og holdes under tilbagesvaling i 72 timer, hvorpå den filtreres. Til filtratet sættes ether og derefter ethe-risk hydrogenchlorid, og det herved fremkomne bundfald samles og omkrystalliseres flere gange fra methanol/butanon 35 og butanon, hvilket giver ethyl-4-[4-[4-(hydroxydiphenylmethyl) -1-piperidinyl]-l-oxobutyl]-α,α-dimethylbenzenace-tat-hydrochlorid med smp. 205,5-208°C.
9 2.DK 1537098 · Ο
De her omhandlede forbindelsers fremragende virkning som antihistaminer sammenlignet med kendte forbindelser fremgår af de følgende forsøg, der ær gennem-5 ført på marsvin.
Der anvendes dels forbindelse I, a- (p-ctert.-butylphenyl)-4-(a-hydroxy-a-phenylbenzyl)-1-piperidin-butanol, som er en kendt forbindelse, der er fremstillet som beskrevet i eksempel 1 i USA-pateent-10 skrift nr. 3.878.217, dels forbindelse II, 4—[4— -[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxy-butyl]-a,a-dimethylbenzeneddikesyre, som ér fremstillet ifølge opfindelsen som beskrevet i eksempels.
De to forbindelser afprøves for deres 15 antihistamin-virkning overfor med histamin-di- phosphat fremkaldte hudvabler hos marsvin (1,0 μg pr. vabel). De to forbindelser indgives intravenøst i en dosis på 0,8 mg pr. kg i begge tilfælde.
Ved afprøvning på denne måde udviser for-20 bindelse I sin antihistamin-virkning gradvist og når maksimal effekt (85%'s inhibering) 240 minutter efter indgivelsen. I modsætning hertil fremkalder forbindelse II en hurtigt indtrædende virkning mod de histamin-inducerede vabler og når sin 25 maksimale effekt (90%'s inhibering) allerede 30 minutter efter indgivelsen.
Det ses, at forbindelse II under de beskrevne betingelser er langt den hurtigst virkende antihistaminsk virksomme forbindelse, hvorfor den 30 må anses for at have en overraskende fordelagtig virkning i forhold til den kendte forbindelse, når der ønskes en hurtigt indtrædende virkning.
35

Claims (2)

10 DK 153709B o PATENTKRAV.
1. Analogifremgangsmåde til fremstilling af 4-sub-stituerede piperidinoalkanolderivater af formlen (I) 6" Nr oh ch3 10 (CH2) 3-CH-^~~^-C-R3
3. CH hvor R er -COOH eller -COO-alkyl? hvor alkylgruppen indeholder 1-6 carbonatomer og er ligekædet eller forgrenet, eller farmaceutisk acceptable salte af disse forbindelser, 15 kendetegnet ved, at den tilsvarende alkanon reduceres selektivt, hvorefter, om ønsket, en fremstillet 3 forbindelse, hvori R er -COO-alkyl, omdannes til en for- 3 bmdelse, hvori R er -COOH, ved base-hydrolyse, og/eller den dannede forbindelse omdannes til et farmaceutisk accep-2o tabelt salt deraf.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der anvendes sådanne udgangsforbindelser, at den opnåede forbindelse bliver ethyl-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-25 -hydroxybutyl]-α,α-dimethylbenzen-acetat eller 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxy-buty1]-u,a-dimethylbenzeneddikesyre. 1 35
DK132980A 1979-04-10 1980-03-27 Analogifremgangsmaade til fremstilling af 4-substituerede piperidinoalkanolderivater DK153709C (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/028,813 US4254129A (en) 1979-04-10 1979-04-10 Piperidine derivatives
US2881379 1979-04-10

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DK132980A DK132980A (da) 1980-10-11
DK153709B true DK153709B (da) 1988-08-22
DK153709C DK153709C (da) 1988-12-27

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JP (1) JPS55141469A (da)
AT (1) AT376208B (da)
AU (1) AU531146B2 (da)
BE (1) BE882703A (da)
CA (1) CA1123438A (da)
CH (1) CH643245A5 (da)
DE (1) DE3007498A1 (da)
DK (1) DK153709C (da)
ES (1) ES489934A0 (da)
FR (1) FR2453854A1 (da)
IL (1) IL59158A (da)
IT (1) IT1143960B (da)
NL (2) NL190580C (da)
NO (2) NO154521C (da)
NZ (1) NZ192653A (da)
PH (1) PH17023A (da)
SE (1) SE448726B (da)
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IL59158A (en) 1984-04-30
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