DK158980B - Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf - Google Patents

Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf Download PDF

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DK158980B
DK158980B DK119675A DK119675A DK158980B DK 158980 B DK158980 B DK 158980B DK 119675 A DK119675 A DK 119675A DK 119675 A DK119675 A DK 119675A DK 158980 B DK158980 B DK 158980B
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bis
benzamide
piperidylmethyl
acid
acid addition
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Elden Harris Banitt
William Robert Bronn
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Riker Laboratories Inc
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
    • C07D211/26—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 nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
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    • 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
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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Description

i
DK 158980 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf.
Den omhandlede forbindelse og farmaceutisk acceptable syreadditionssalte deraf er aktive antiarrhytmimidler.
I US patentskrift nr. 3 719 687 er beskrevet visse benz-amider, der er substituerede i den aromatiske ring med I, 1-dihydroperfluoralkoxygrupper. Den omhandlede forbin-10 delse afviger fra de derfra kendte ved, at 1) benzamidonitrogenatomet er bundet gennem en methylen-gruppe til carbonatomet i piperidinringen, 15 2) den omhandlede forbindelse er en sekundær amin, og 3) i den omhandlede forbindelse er der kun et carbonatom, der forbinder benzamidonitrogenatomet til piperidin-ringen. Endvidere har den omhandlede forbindelse et on asymmetrisk carbonatom.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er mere antiarrhytmisk aktive end de fra US patentskrift nr. 3 719 687 kendte forbindelser. Acetatet af 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)-benzamid har vist sig at have en ED^-værdi på 48 umol/kg i den prøve, der er gengivet af Baritt et al. i J. Med. Chem., 20, 821-826, se tabel III, sidste spalte, forbindelse nr. 33. Prøven er også udført med to af de 30 fra US patentskriftet kendte forbindelser, forbindelserne fra eksempel 43 og 56. Disse forbindelser har ED^Q-værdi-er på 62 umol/kg henholdsvis 79 umol/kg og er således mindre aktive.
35
OK 158980 B
2
Den omhandlede forbindelse kan spaltes i de optisk aktive enantiomere på kendt måde.
Forbindelserne kan anvendes direkte eller i form af et 5 farmaceutisk acceptabelt syreadditionssalt, især som et opløseligt salt af eddikesyre, saltsyre, svovlsyre eller phosphorsyre. Andre salte er kombinationer med hydrogen-bromidsyre, sulfaminsyre, methansulfonsyre, benzensulfon-syre, ethandisulfonsyre, citronsyre, maleinsyre, oxalsy-10 re, ravsyre, æblesyre, fumarsyre og vinsyre.
De omhandlede forbindelsers antiarrhytmivirkning manifesterer sig ved deres evne til at blokere chloroform-induceret ventriculær flimren hos mus ved prøvepro-15 ceduren, beskrevet af J. W. Lawson, J. Pharmacol. Exp. Therap. 160:22-32, 1968.
Ved klinisk praksis vil den omhandlede forbindelse normalt blive indgivet som antiarrhytmimiddel oralt eller 20 ved injektion af et farmaceutisk præparat omfattende den aktive ingrediens i form af den frie base eller et af de sædvanlige terapeutisk acceptable salte, f.eks. acetatet eller hydrochloridet, i kombination med en farmaceutisk acceptabel bærer.
25 Bæreren kan være et fast, halvfast eller flydende fortyndingsmiddel eller en nedsvælgelig kapsel.
Til parenteral indgivelse ved injektion anvendes for-30 trinsvis en vandig opløsning, i reglen en saltvandsopløsning af et vandopløseligt farmaceutisk acceptabelt salt af den aktive forbindelse og eventuelt også et stabiliseringsmiddel og/eller en puffer, f.eks. natriumacetat.
35 Endvidere udviser den omhandlede forbindelse også en lo-kalanæstetisk virkning, f.eks. ved topisk påføring eller ved injektion. Den lokalanæstetiske virkning er observe- ret ved anvendelse af cornealrefleksprøven på kaniner.
Denne prøvemetode er beskrevet af F. P. Luduena og J. O.
Hoppe, J. Pharmocol. Ex. Therap., 104:40, 1952.
3
DK 158980 B
5 Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte.
Ved fremgangsmåden b) udføres reaktionen i et inert opløsningsmiddel, såsom benzen, ethylenglycoldimethylether, 10 toluen eller diethylether. Når Z er chlor, anvendes fortrinsvis en syreacceptor, f.eks. en tertiær amin. Når Z betegner en 1,1-dihydroperfluoralkoxygruppe, udføres reaktionen i reglen ved at opvarme reaktanterne under tilbagesvaling uden opløsningsmiddel eller i et inert op-15 løsningsmiddel, såsom ethylenglycoldimethylether, efterfulgt af isolation af produktet.
Ved fremgangsmåden a) (1) anvendes reaktionsbetingelser, der minder om betingelserne i den ovenfor beskrevne 1-20 trinsmetode, afhængigt af hvorvidt z betegner chlor eller 1,1-dihydroperfluoralkoxy. Der reduceres derpå (2) selektivt katalytisk til den tilsvarende piperidin med formlen I. Den foretrukne katalysator ved den katalytiske reduktion er platinoxid. Reduktionen gennemføres i reglen un-25 der sure betingelser, f.eks. i eddikesyre som opløsningsmiddel i nærvær af hydrogenchlorid.
Forbindelserne med formel II kan bekvemt fremstilles ud fra de tilsvarende syrer, dvs. forbindelser med formlen 30 II, hvori Z er OH, og disse syrer er kendte, f.eks. fra US patentskrift nr. 3 655 728. Forbindelserne, hvori Z betegner chlor, kan fremstilles ved tilbagesvaling af syrerne med et overskud af thionylchlorid, i nærvær af en ringe mængde dimethylformamid. Overskuddet af thionyl-35 chlorid fjernes derpå ved destillation. Forbindelserne med formlen II, hvori Z betegner 1,1-dihydroperfluoralkoxygruppe, er beskrevet i US patentskrift nr. 3 655 728 og
.DK 158980 B
4 kan fremstilles ved omsætning af hydroxy- og polyhydroxy-aromatiske syrer med alkyleringsmidler med formlen V CF3S020CH2Rf 5 i nærvær af natriumbicarbonat, kaliumbicarbonat eller andre metalbicrbonater i et inert opløsningsmiddel, såsom acetone. Den resulterende 1,1-dihydroperfluoralkylester kan hydrolyseres til den frie syre (forbindelser med 10 formlen II, hvori Z betegner OH).
Forbindelserne med formlerne III og IIIA er generelt kendte eller kan let fremstilles på kendt måde. Således kan forbindelsen III fremstilles ud fra den tilsvarende 15 forbindelse IIIA ved katalytisk reduktion. Yderligere kan forbindelserne III og IIIA fremstilles ved reduktion af de tilsvarende oximer, der igen kan fremstilles ud fra de tilsvarende aldehyder ved omsætning med hydroxylamin-hydrochlorid.
20
Opfindelsen forklares nærmere ved hjælp af nedenstående eksempler.
EKSEMPEL 1 25
En opløsning af 0,20 mol (21,6 g ) 2-aminomethylpyridin i 200 ml ethylenglycoldimethylether behandledes dråbevis i 40 minutter med 0,10 mol (40 g) 2,2,2-trifluorethyl-2,5-bis(2,2,2-trifluorethoxy)benzoat, og den resulterende 30 blanding omrørtes ved ca. 25 °C i ca. 60 timer, opvarmedes og holdtes ved tilbagesvalingstemperaturen i ca. 1 time. Derpå inddampedes blandingen til tørhed, triturere-des med vand, og det dannede produkt filtreredes. Det faste stof skylledes grundigt med vand, tørredes i en ovn 35 under vakuum og rekrystalliseredes fra en 5:3 blanding af cyclohexan og carbontetrachlorid efter behandling med affarvende aktivt kul. Efter omhyggelig tørring opnåedes
DK 158980 B
5 2.5- bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benz-amid, som et fast hvidt stof, smp. 102-104 °C.
Dette produkt omdannedes til hydrochloridet ved omsætning 5 i diethylether med en opløsning af hydrogenchloridgas i diethylether. Omkrystallisation af produktet f:ra en blanding af isopropanol og diethylether efter behandling med af farvende aktivt kul gav et rent hvidt salt, smp. 190-193 °C.
10
Det følgende eksempel illustrerer reduktionen af mellemproduktet med formlen IV til dannelse af forbindelsen med formlen I.
15 EKSEMPEL 2
En opløsning af 40,8 g (0,01 mol) N-(2-pyridylmethyl)- 2.5- bis(2,2,2-trifluorethoxy)benzamid i 600 ml eddikesyre blev under ^ sat til en pasta af 0,4 g platinoxid i 20 eddikesyre og hydrogeneret på et Parr-apparat. Efter optagelse af den teoretiske mængde hydrogen blev blandingen filtreret til fjernelse af katalysatoren, og filtratet blev genfiltreret med tilsat supercell. Inddampning af filtratet under vakuum efterlod en viskos sirup, som 25 størknede ved triturering med isopropylether. Det faste stof blev samlet ved sugningsfiltrering og opløst i varm isopropanol. Udkrystallisering blev indledt ved tilsætning af isopropylether til uklarhedspunktet. Det rensede produkt, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluor- 30 ethoxy)benzamid-acetat blev samlet som et hvidt kornet fast stof, smp. 145-147 °C, udbyttet 35,8 g (76%). Denne reduktion kan også udføres i ethanol under anvendelse af foruddannet hydrochlorid af pyridylmethylbenzamid-ud-gangsmaterialet.
35 6
DK 158980 B
EKSEMPEL 3
Under en nitrogenatmosfære behandledes 0,249 mol (28,4 g) 2-aminomethylpiperidin i 25 minutter med 0,0249 (10,0 g) 5 2,2,2-trifluorethyl-2,5-bis-(2,2,2-trifluorethoxy)benzo- at. Efter tre timer tilsattes 50 ml benzen, og der omrør-tes i ca. 40 timer ved 45 °C. Blandingen koncentreredes derpå under vakuum. Remanensen størknede efter afkøling, vanddampdestilleredes og separeredes ved filtrering og 10 ekstraheredes med dichlormethan, udvaskedes med mættet natriumchloridopløsning, hvorpå det organiske lag blev tørret over vandfri magnesiumsulfat. Magnesiumsulfat fjernedes ved filtrering, og der tilsattes 4 ml 8,4 N hy-drogenchlorid i isopropanol til dichlormethanopløsningen 15 under omrøring. Efter to timer afkøledes blandingen til ca. 0 °C, og det rå produkt opsamledes ved filtrering, udvaskedes med diethylether og tørredes i en vakuumovn.
Efter behandling med affarvende aktivt kul og krystallisation fra en blanding af lige dele isopropanol og etha- 20 nol opnåedes produktet 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benzamid-hydrochiorid, smp. 228-229 °C.
EKSEMPEL 4 25 10 ml isopropanol anvendtes til at opløse 0,005 mol (2,07 g) 2,5-bis(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)- benzamid, og der tilsattes 1 ækvivalent eddikesyre opløst i 1 ml isopropanol. Ved afkøling opnåedes et fast stof, 30 der separeredes fra ved filtrering. Produktet omkrystalliseredes fra isopropanol til dannelse af acetatet, smp. 145-147 °C.
Analogt med eksempel 4 fremstilledes en række farmaceu-35 tisk acceptable salte af forbindelsen 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benzamid.
Deres opløselighed og data fremgår af nedenstående tabel
DK 158980 B
7 1.
iMBE L I
5 Opløselighed
Eks. Syre i varmt vand smp., °C
5 H2S04 >2% 100 6 H3P04 >5% 210 10 7 CH = CH >5% 122-124
I I
HOOC COOH
8 CH3S03H >10% 115-121 9 HCOOH >10% 171-172 15 10 uopl. ----- 11 CH3(CH2)14C00H uopl. ----- 12 ch3ch2cooh >10% ----- 20 13 CHoCHoC00H > 5% I Z /
COOH
25 30 35

Claims (1)

15 H <0 og (2) isolerer forbindelsen I, hvorefter en ved frem-20 gangsmåde a) eller b) fremstillet forbindelse I om ønsket omsættes med en syre til dannelse af et farmaceutisk acceptabelt syreadditionssalt, eventuelt efterfulgt af overføring i en anden isomer form deraf, herunder blandinger, på i og for sig kendt måde. 25 30 35
DK119675A 1974-04-01 1975-03-21 Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf DK158980C (da)

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US457099A US3900481A (en) 1974-04-01 1974-04-01 Derivatives of pyrrolidine and piperidine
US45709974 1974-04-01

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DK158980B true DK158980B (da) 1990-08-13
DK158980C DK158980C (da) 1991-01-07

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FR2265366A1 (da) 1975-10-24
CS209846B2 (en) 1981-12-31
NL186633C (nl) 1991-01-16
IE41224L (en) 1975-10-01
AU7957875A (en) 1976-09-30
JPS50137975A (da) 1975-11-01
NO144262C (no) 1981-07-29
NO144262B (no) 1981-04-21
GB1508015A (en) 1978-04-19
DK158980C (da) 1991-01-07
PL95576B1 (pl) 1977-10-31
FR2265366B1 (da) 1980-01-11
JPS5865268A (ja) 1983-04-18
JPS5858347B2 (ja) 1983-12-24
DE2513916A1 (de) 1975-10-09
CA1054602A (en) 1979-05-15
DK119675A (da) 1975-10-02
CH618425A5 (da) 1980-07-31
IL46967A0 (en) 1975-05-22
NO750976L (da) 1975-10-02
ES435870A1 (es) 1976-12-16
BE827354A (fr) 1975-09-29
IL46967A (en) 1978-09-29
IE41224B1 (en) 1979-11-21
SU668599A3 (ru) 1979-06-15
SE7503262L (da) 1975-10-02
JPS5827268B2 (ja) 1983-06-08
DE2513916C2 (de) 1982-12-23
NL186633B (nl) 1990-08-16
US3900481A (en) 1975-08-19
OA04912A (fr) 1980-10-31
SE391336B (sv) 1977-02-14
AR210990A1 (es) 1977-10-14
ZA751040B (en) 1976-01-28
NL7503389A (nl) 1975-10-03
HU169762B (da) 1977-02-28

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