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 HerstellungInfo
- 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
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
DEUTSCHES
PATENTAMT
Int. Cl.:
Deutsche KL:
Nummer:
Aktenzeichen:
Anmeldetag:
Auslegetag:
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
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
seine Salze sowie Verfahren zu deren Herstellung
Anmelder:
C. H. Boehringer Sohn, Chemische Fabrik,
6507 Ingelheim
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).
**) Siehe Arzneimittelforschung, Bd. 12, S. 176, rechte Spalte unter IV (1962).
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)
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
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) |
-
1961
- 1961-02-11 DE DEP1270A patent/DE1270561B/de active Pending
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