DE1270561B - 1-Allyl-4-phenyl-4-propoxycarbonyl-piperidin, seine Salze sowie Verfahren zu deren Herstellung - Google Patents

1-Allyl-4-phenyl-4-propoxycarbonyl-piperidin, seine Salze sowie Verfahren zu deren Herstellung

Info

Publication number
DE1270561B
DE1270561B DEP1270A DE1270561A DE1270561B DE 1270561 B DE1270561 B DE 1270561B DE P1270 A DEP1270 A DE P1270A DE 1270561 A DE1270561 A DE 1270561A DE 1270561 B DE1270561 B DE 1270561B
Authority
DE
Germany
Prior art keywords
piperidine
propoxycarbonyl
allyl
phenyl
salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
DEP1270A
Other languages
English (en)
Inventor
Dr Karl Zeile
Dipl-Chem Dr Herbert Merz
Dr Kurt Freter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CH Boehringer Sohn AG and Co KG
Original Assignee
CH Boehringer Sohn AG and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CH Boehringer Sohn AG and Co KG filed Critical CH Boehringer Sohn AG and Co KG
Priority to DEP1270A priority Critical patent/DE1270561B/de
Publication of DE1270561B publication Critical patent/DE1270561B/de
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • 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
    • C07D211/34—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

BUNDESREPUBLIK DEUTSCHLAND
DEUTSCHES
PATENTAMT
AUSLEGESCHRIFT
Int. Cl.:
Deutsche KL:
Nummer:
Aktenzeichen:
Anmeldetag:
Auslegetag:
C07d
A61k
12 ρ-1/01
30 h-2/36
P 12 70 561.2-44
11. Februar 1961
20.Juni 1968
Die vorliegende Erfindung betrifft l-AUyl-4-phenyl-4-propoxycarbonyl-piperidin der Formel
CH2 C03
CH2 — CH = CH2
und dessen Säureadditionssalze sowie ein Verfahren zu deren Herstellung.
Die erfindungsgemäße Verbindung kann nach an sich bekannten Methoden hergestellt werden, beispielsweise durch Alkylierung von 4-Phenyl-4-propoxycarbonyl-piperidin mit einem Allylhalogenid.
Die Alkylierung wird vorzugsweise in Gegenwart eines organischen Lösungsmittels und einer schwachen Base, beispielsweise Natriumbicarbonat, bei Temperaturen zwischen 50 und 150°C durchgeführt. Die Reaktionspartner können hierbei im Molverhältnis 1 : 1 eingesetzt werden; vorzugsweise wird jedoch das Alkylierungsmittel im Überschuß angewendet.
Das so erhaltene l-Allyl-4-phenyl-4-propoxycarbonyl-piperidin kann in üblicher Weise in seine Säureadditionssalze übergeführt werden.
Die erfindungsgemäße Verbindung besitzt eine ausgeprägte morphinantagonistische Wirkung und vermag bereits in außerordentlich kleinen Dosen die Wirkungen des Morphins aufzuheben. Dadurch unterscheidet sich diese Verbindung in überraschender Weise von den aus der Literatur bekannten Verbindungen
l-AUyM-phenyM-äthoxycarbonyl-piperidinhydrochlorid (A),
l-Methyl^-phenyM-carbäthoxy-piperidinhydrochlorid (B),
l-(n-Octyl)-4-phenyl-4-butoxycarbonylpiperidin (C),
1-3-Hydroxy-N-allyl-morphinan (D).
Die der erfindiingsgemäßen Verbindung nächst verwandle Verbindung, das l-Allyl^-phenyM-äth-
1 -AllyM-phenyM-propoxycarbonyl-piperidin, .
seine Salze sowie Verfahren zu deren Herstellung
Anmelder:
C. H. Boehringer Sohn, Chemische Fabrik,
6507 Ingelheim
Als Erfinder benannt:
Dr. Karl Zeile,
Dipl.-Chem. Dr. Herbert Merz,
Dr. Kurt Freter, 6507 Ingelheim
oxycarbonyl-piperidin-hydrochlorid (A), besitzt keine antagonistischen und kaum analgetische Eigenschaften [vgl. P. J. C ο s t a und D. D. Bonnycastle, Pharmacology and Experimental Therapeutics, Bd. 113, S. 310 ff. (1957)].
Die überlegene bzw. andersartige Wirkung dieser Verbindung gegenüber den drei weiteren zum Vergleich herangezogenen Verbindungen (B), (C) und (D) geht aus der folgenden Tabelle hervor. Die dort angegebenen Zahlenwerte für die morphinantagonistische Wirkung wurde auf folgendem Wege bestimmt: Mäuse erhalten eine Dosis von 15 mg/kg Morphin subkutan injiziert; dies ist diejenige Dosis, bei der 50°/<> der Tiere keinerlei Schmerzreaktion zeigt (ED50). Injiziert man jetzt zusätzlich einen Morphinantagonisten, so läßt sich die durch Morphin hervorgerufene Analgesie abschwächen bzw. ganz aufheben.
Die LOm wurde nach der Methode von G. K ä r b e r [Archiv für experimentelle Pathologie und Pharmakologie, Bd. 162, S. 480 (1931)] an weißen Mäusen bestimmt.
809 560/494
B Morphinantagonistische Wirkung Prozentsatz 0 LD50S-C. Therapeutischer
Verbindung Injektion in mg/kg nach Gabe der analgesierten Tiere 0 Index*)
von 15 mg/kg Morphin s. c. 0 mg/kg
l-AUyl-4-phenyl- - 30
4-propoxycarbonyl- C 50
piperidin-hydro- 0
bromid D 50 mg/kg 0
1 mg/kg 20
0,1 mg/kg 20
0,01 mg/kg 10 860 860
1 r/kg 10
0,1 r/kg 20
0,01 r/kg mehr als 120 mg/kg vermögen nicht, die Wirkung
von 50 mg / kg Morphinsulfat aufzuheben
(Bulletin of the World Health Organization,
Bd. 14, S. 374 [1946])
160 mg/kg vermögen nicht, die Wirkung von 150 —
15 mg/kg Morphin s. c. aufzuheben
10 mg/kg 565 —
1 mg/kg
200 r/kg
100 r/kg 60**) 300
30 r/kg
*) Der therapeutische Index wurde errechnet als Quotient aus LD50: diejenige Dosis, bei der die analgetische Wirkung des Morphins
noch gerade völlig aufgehoben wird.
**) Siehe Arzneimittelforschung, Bd. 12, S. 176, rechte Spalte unter IV (1962).
Beispiel
l-Allyl-^phenyM-propoxycarbonyl-piperidinhydrobromid
/\ O
2,47 g (0,010 Mol)
piperidin werden in 20 ml Äthanol gelöst, mit 1,21 g (0,010 Mol) Allylbromid und 0,95 g (0,011 Mol) Natriumbicarbonat versetzt und unter Rühren 1 Stunde unter Rückfluß erhitzt. Nach dem Abkühlen wird abfiltriert, der Alkohol im Vakuum entfernt und der Rückstand mit 2 n-Bromwasserstoffsäure angesäuert. Dabei scheidet sich das Hydrobromid des 1 - Allyl-4-phenyl -4-propoxycarbonyl-piperidins ab, das aus Wasser umkristallisiert wird. Ausbeute: 3,3 g (90% der Theorie) vom Fp. 149 bis 150 C.

Claims (2)

Patentansprüche:
1. l-Allyl-^phenyl-^propoxycarbonyl-piperidin der Formel
C — O — CH2 — CH2 — CH3
CH, — CH = CH,
und seine Säureadditionssalze.
2. Verfahren zur Herstellung von 1-Allyl-4-phenyI-4-propoxycarbonyl-piperidin und dessen Säureadditionssalzen, dadurch gekennzeichnet, daß man in an sich bekannter Weise 4-Phenyl-4-propoxycarbonyl-piperidin, vorzugsweise in Gegenwart eines Lösungsmittels und einer schwachen Base,. mit mindestens der äquimolaren Menge eines Allylhalogenids auf 50 bis 150 C erhitzt, worauf man das so erhaltene Produkt gegebenenfalls mit einer Säure in eines seiner Salze überfuhrt.
809 560/494 6.68 © Bundesdrnckerei Berlin
DEP1270A 1961-02-11 1961-02-11 1-Allyl-4-phenyl-4-propoxycarbonyl-piperidin, seine Salze sowie Verfahren zu deren Herstellung Pending DE1270561B (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DEP1270A DE1270561B (de) 1961-02-11 1961-02-11 1-Allyl-4-phenyl-4-propoxycarbonyl-piperidin, seine Salze sowie Verfahren zu deren Herstellung

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEP1270A DE1270561B (de) 1961-02-11 1961-02-11 1-Allyl-4-phenyl-4-propoxycarbonyl-piperidin, seine Salze sowie Verfahren zu deren Herstellung

Publications (1)

Publication Number Publication Date
DE1270561B true DE1270561B (de) 1968-06-20

Family

ID=5661007

Family Applications (1)

Application Number Title Priority Date Filing Date
DEP1270A Pending DE1270561B (de) 1961-02-11 1961-02-11 1-Allyl-4-phenyl-4-propoxycarbonyl-piperidin, seine Salze sowie Verfahren zu deren Herstellung

Country Status (1)

Country Link
DE (1) DE1270561B (de)

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